Explain the bronchial asthma

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I now have comprehensive, authoritative content from both Harrison's Principles of Internal Medicine (22nd Ed, 2025) and Goldman-Cecil Medicine. Here is a detailed, well-structured explanation:

Bronchial Asthma

Definition

Asthma is a clinical syndrome of unknown etiology characterized by recurrent episodes of airway obstruction that resolve spontaneously or as a result of treatment. These changes occur in the setting of various types of airway inflammation thought to reflect specific endotypes. Although airway obstruction is largely reversible, some changes leading to obstruction may become irreversible over time.

Goldman-Cecil Medicine, p. 879

Epidemiology

Affects approximately 8% of the adult US population and an estimated 340 million people worldwide, with ~420,000 annual deaths
More common in boys than girls before puberty; after puberty, women > men (rate ratio ~1.8:1)
Most cases begin before age 25, but new-onset asthma can develop at any age
Worldwide prevalence increased >50% in the latter half of the 20th century, particularly in countries adopting industrialized lifestyles; prevalence has plateaued since ~2015
Growing up on a farm in close contact with cattle is associated with a markedly lower risk
Goldman-Cecil Medicine, p. 880

Pathobiology

Genetics

Asthma has about 60% heritability (twin studies). Multiple genome-wide association studies have identified genetic loci related to immune mechanisms, confirming that both genetic and environmental factors play a role.

Pathology and Endotypes

The asthma syndrome shows marked heterogeneity. Classically, two forms were recognized (atopic and non-atopic), but this is an oversimplification. Multiple endotypes underlie the common signs and symptoms:

1. Atopic (Allergic) Asthma - the most common subtype

IgE-mediated sensitization to environmental allergens
Present in almost all school-aged children with asthma and ~50% of adult asthmatics
Pathologic features: airway inflammation and remodeling - epithelial fragility, edema, mucosal hyperemia, subepithelial reticular basement thickening (collagen III and IV deposition)
In severe/chronic disease: airway wall thickening from smooth muscle hyperplasia, mucus gland hypertrophy, and subepithelial angiogenesis
Inflammatory infiltrate: eosinophils, CD4+ T-lymphocytes, mast cells, macrophages
IgE-coated mast cells in the airway epithelium and lumen are hallmarks

2. Non-Atopic (Non-Allergic) Asthma

Triggered by irritants, pollutants, microbes, viruses
Driven by neutrophilic inflammation, Th1 and Th17 cells
Mediated by IL-6, IL-17, TNF-alpha, IL-1beta, IL-8

3. Pauci-Granulocytic Asthma

A small subset with pathologic changes but no tissue infiltration by inflammatory cells; etiology unclear

Pathophysiology

Mechanisms of Airway Obstruction

Three major processes can occur individually or simultaneously:

1. Airway Hyperresponsiveness The hallmark of asthma. Defined as an exaggerated narrowing response to agents that cause no response in unaffected individuals. Occurs at the level of airway smooth muscle (shown by hyperresponsiveness to histamine or methacholine). It can also arise from indirect activation of inflammatory cells that release bronchoconstricting mediators.

2. Airway Inflammation

Type 2 (T2-high) inflammation: driven by allergens activating dendritic cells → Th2 cells and ILC2 cells → release of IL-4, IL-5, IL-13 → eosinophil recruitment, IgE production, mast cell activation → bronchoconstriction, mucus secretion, airway remodeling
Non-Type 2 (T2-low) inflammation: triggered by irritants, pollutants, viruses → Th1/Th17 cells, neutrophilic inflammation → IL-17, IL-6, IL-8 → smooth-muscle constriction

3. Airway Remodeling Chronic inflammation leads to structural changes: subepithelial fibrosis, smooth-muscle hypertrophy/hyperplasia, goblet cell hyperplasia (excess mucus), and angiogenesis.

Inflammatory cells and mediators in Type 2 and Non-Type 2 asthma

Figure: Type 2 inflammation (left) driven by allergens via Th2 cells, mast cells, eosinophils and ILC2 cells producing IL-4, IL-5, IL-13; Non-Type 2 inflammation (right) driven by irritants/viruses via neutrophils, Th17/Th1 cells. Both converge on smooth-muscle contraction and airway hyperresponsiveness. - Harrison's 22E, Fig. 298-3

Key Mediators

Mediator	Source	Effect
IL-4, IL-5, IL-13	Th2 cells, ILC2	Core T2 cytokines; IgE switching, eosinophil recruitment, mucus
TSLP, IL-25, IL-33	Airway epithelium	Alarm signals (alarmins); amplify T2 cascade
Cysteinyl leukotrienes (LTC4, LTD4, LTE4)	Eosinophils, mast cells	Potent smooth-muscle constrictors, mucus secretion, microvascular leakage
Histamine	Mast cells	Bronchoconstriction, vasodilation
PGD2	Mast cells	Activates CRTH2 receptors on T2/ILC2/eosinophil cells; upregulates T2 inflammation
LTB4	Neutrophils	Neutrophil chemoattractant
TNF-alpha, IL-6, IL-17, IL-8	Neutrophils, macrophages	Non-T2 inflammation

Harrison's 22E, p. 2262

Risk Factors and Triggers

Development Risk Factors:

Allergen exposure in atopic individuals
Occupational exposures
Air pollution
Viral and Mycoplasma infections
Tobacco smoke
Obesity
Diet
Fungi (allergic airway mycoses)
Reactive airway dysfunction syndrome (RADS)
High-intensity exercise in elite athletes

Triggers of Acute Airway Narrowing:

Allergens
Irritants
Viral infections (most common cause of exacerbations)
Exercise and cold, dry air
Air pollution
Drugs (NSAIDs, aspirin, beta-blockers)
Occupational exposures
Hormonal changes
Pregnancy

Clinical Features

Symptoms:

Episodic wheezing, particularly expiratory
Dyspnea (breathlessness)
Chest tightness
Cough (dry or productive), especially at night or early morning
Symptoms often worse at night (nocturnal asthma)

Signs:

Prolonged expiration and wheeze on auscultation
Use of accessory muscles in severe attacks
Pulsus paradoxus in severe/life-threatening attacks
Cyanosis (late, ominous sign)

Investigations

Pulmonary Function Tests (PFTs) - cornerstone of diagnosis:

Obstructive pattern: reduced FEV1, reduced FEV1/FVC ratio
Reversibility: ≥12% and ≥200 mL improvement in FEV1 after bronchodilator - confirms diagnosis
Methacholine challenge test: positive (PC20 ≤8 mg/mL) if PFTs normal but asthma suspected

Blood Findings:

Eosinophilia (common in T2-high phenotype)
Elevated serum IgE (total and specific IgE via RAST)
FeNO (fractional exhaled nitric oxide): elevated in eosinophilic/T2-high asthma; used to guide treatment

Radiology:

Chest X-ray usually normal
Severe asthma: hyperinflation (depressed diaphragm, lucent lung fields)
Complications: pneumomediastinum, subcutaneous emphysema, pneumothorax may be seen

Arterial Blood Gas (ABG) in Acute Severe Asthma:

Initially: hypoxemia (PaO2 55-70 mmHg) + hypocapnia (PaCO2 25-35 mmHg) + respiratory alkalosis
As severity worsens: PaCO2 normalizes or rises - ominous sign indicating impending respiratory failure
A "normal" PaCO2 in a patient with several days of severe airflow obstruction signals that respiratory failure may be imminent

Sputum:

May be clear or colored (color does not always indicate infection)
Microscopy: eosinophils, Charcot-Leyden crystals, Curschmann spirals

ECG:

Usually normal (sinus tachycardia) in mild/moderate attacks
Severe attacks: right axis deviation, right bundle branch block, "P pulmonale", ST-T changes (resolve with treatment)
Goldman-Cecil Medicine, p. 882-884

Treatment

Goals of Therapy (GINA/NAEPP)

Reduction of symptoms to ≤2 times/week
Nighttime awakenings ≤2 times/month
Reliever use ≤2 times/week (except pre-exercise)
No more than 1 exacerbation/year
Optimization of lung function (FEV1/PEF)
Maintenance of normal daily activities
Minimal or no medication side effects

Non-Pharmacological Measures

Trigger avoidance: remove pets, pest control, impermeable mattress covers for dust mites, smoking cessation
Allergen immunotherapy: reduces IgE-mediated reactions; effective for mild-moderate allergic asthma under control
Vaccination: annual influenza, pneumococcal (all adult asthmatics), COVID-19, RSV vaccines
Treat comorbidities: allergic rhinitis, GERD, obesity, obstructive sleep apnea

Pharmacotherapy

Reliever (Rescue) Medications

Short-Acting Beta-2 Agonists (SABAs)

Salbutamol (albuterol), terbutaline
Onset 5-10 min, duration 4-8 hours
First-line for acute symptom relief; all patients should have a SABA rescue inhaler

Short-Acting Anticholinergics

Ipratropium bromide - used in acute exacerbations, especially in combination with SABAs

Systemic Corticosteroids (acute severe attacks)

IV hydrocortisone 2 mg/kg bolus then 0.5 mg/kg/hr for non-life-threatening severe exacerbations
IV methylprednisolone 125 mg every 6 hours for life-threatening exacerbations
Oral prednisolone for outpatient step-up; taper over 1-3 weeks

Controller (Preventive) Medications

Inhaled Corticosteroids (ICS) - cornerstone of preventive therapy

Beclomethasone, budesonide, fluticasone
Most effective anti-inflammatory agents; reduce exacerbations, symptoms, and improve lung function

Long-Acting Beta-2 Agonists (LABAs)

Salmeterol, formoterol
Always used in combination with ICS, never as monotherapy

Leukotriene Receptor Antagonists (LTRAs)

Montelukast, zafirlukast
Useful add-on therapy, especially in aspirin-exacerbated asthma and exercise-induced asthma

Theophylline

Narrow therapeutic window; used as add-on in patients not controlled on ICS/LABA; blood level monitoring required

Biologic (Monoclonal Antibody) Therapies

For severe asthma inadequately controlled on high-dose ICS/LABA:

Drug	Target	Indication
Omalizumab (Xolair)	Anti-IgE	Moderate-severe allergic asthma with elevated IgE; reduces exacerbations; risk of anaphylaxis - monitor 30-60 min post-injection
Mepolizumab (Nucala)	Anti-IL-5	Severe eosinophilic asthma (eosinophils >150/µL); 100 mg SC every 4 weeks; ~50% reduction in exacerbations
Reslizumab (Cinqair)	Anti-IL-5	Severe eosinophilic asthma; 3 mg/kg IV every 4 weeks
Benralizumab (Fasenra)	Anti-IL-5Rα	Near-complete eosinophil/basophil depletion from blood and lung tissue
Dupilumab (Dupixent)	Anti-IL-4Rα (blocks IL-4 + IL-13)	T2-high asthma; also effective in OCS-dependent asthma regardless of biomarkers; also approved for COPD with eosinophilia
Tezepelumab (Tezspire)	Anti-TSLP	Broadest indication - reduces exacerbations even in non-T2 asthma without elevated FeNO or eosinophils; 50-70% exacerbation reduction

Harrison's 22E, p. 2581-2589

Stepwise GINA Approach (Simplified)

Step	Treatment
Step 1 (Mild intermittent)	SABA as needed; consider low-dose ICS
Step 2 (Mild persistent)	Low-dose ICS + SABA reliever
Step 3 (Moderate persistent)	Low-dose ICS/LABA or medium-dose ICS
Step 4 (Moderate-severe)	Medium- to high-dose ICS/LABA
Step 5 (Severe uncontrolled)	High-dose ICS/LABA + add-on (tiotropium, LTRA, macrolides) + biologic therapy

Special Situations

Asthma attacks: Escalation of bronchodilators + systemic corticosteroids; if no response - ICU referral
Status asthmaticus: Life-threatening attack unresponsive to standard treatment; requires IV methylprednisolone, IV magnesium sulfate, possible intubation
High-risk patients: Prior ICU admission, recent OCS use, >2 hospitalizations/year, history of near-fatal attack
Elderly: Diagnostic challenges due to overlap with COPD and cardiac disease; underdiagnosis common
Asthma-COPD Overlap (ACO): Features of both diseases; ICS-based treatment essential
Pregnancy: Uncontrolled asthma is more dangerous to mother and fetus than asthma medications; continue ICS; salbutamol safe; most biologics category C
Exercise-induced asthma: Pre-treatment with SABA 15 minutes before exercise; ICS for frequent episodes; LTRA also effective

Summary

Bronchial asthma is a chronic inflammatory airway disease with episodic, largely reversible airway obstruction driven by a complex interplay of genetic susceptibility and environmental triggers. Its pathophysiology centers on airway hyperresponsiveness, inflammation (T2-high or T2-low), and remodeling. Diagnosis rests on clinical history and confirmed reversible airflow obstruction on spirometry. Treatment follows a stepwise approach from SABA rescue inhalers through ICS-based controllers to targeted biologic therapies for severe disease.

Sources:

Harrison's Principles of Internal Medicine, 22nd Edition (2025), Chapter 298
Goldman-Cecil Medicine, International Edition, Chapter 75 (Drazen JM & Bel EH)

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