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Bronchiectasis - Comprehensive Answer (Fishman's & Murray & Nadel's)

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Definition

• Fishman's Pulmonary Diseases and Disorders, Ch. 51
• Murray & Nadel's Textbook of Respiratory Medicine, Ch. 69

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Historical Note

• Fishman's, Ch. 51

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Epidemiology

• Prevalence of non-CF bronchiectasis: estimated 52-139 cases per 100,000 in the United States
• Total US cases exceed 110,000
• Prevalence increases with age
• More common in women (1.3-1.6x higher prevalence) and Asians (2.5-3.9x higher than Caucasians and African Americans)
• Prevalence has increased by 8.7% per year
• Similar increasing trends reported in Europe (2004-2013 data)
• Associated with significant economic cost, increased hospitalizations, impaired quality of life, and excess mortality
• Fishman's, Ch. 51

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Pathogenesis

The "Vicious Circle" (Cole's Hypothesis)

1. Initial insult (infection, aspiration, immune defect) causes neutrophilic inflammation
2. Airway destruction in genetically susceptible individuals
3. Anatomic disruption leads to abnormal mucus clearance
4. Impaired clearance enables chronic bacterial colonization
5. Chronic infection propagates further airway inflammation and destruction
6. The cycle perpetuates itself

• Fishman's, Ch. 51

Cellular/Molecular Mechanisms

• Neutrophil recruitment via glycoproteins and IL-8 in response to bacterial pathogens
• Human Neutrophil Elastase (HNE) - a proteolytic enzyme key to bacterial defense but also causes direct tissue damage; damages bronchial walls and promotes goblet cell hyperplasia
• Reactive oxygen intermediates released by neutrophils cause additional oxidative damage
• Direct damage to ciliated airway epithelium disrupts mucociliary clearance
• Biofilm formation by pathogens (especially Pseudomonas aeruginosa): bacteria produce an exopolysaccharide matrix (glycocalyx) that protects them against host immune cells and antibiotics; biofilm bacteria may survive antibiotic concentrations 1000x above MIC
• Quorum sensing by P. aeruginosa allows paracrine gene activation within biofilms, enhancing virulence factor production
• Core microbiome includes not only recognized pathogens (P. aeruginosa, H. influenzae, S. pneumoniae) but also atypical organisms like Veillonella and Prevotella
• Murray & Nadel's, Ch. 69; Fishman's, Ch. 51

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Classification / Morphologic Types

• Murray & Nadel's, Ch. 69; Fishman's, Ch. 51

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Etiology

1. Postinfectious (Most Common Historically)

• Necrotizing bacterial pneumonias (Klebsiella, Staphylococcus, anaerobes)
• Pertussis and measles (historically major causes in childhood; associative, not always causal)
• Adenovirus (especially types 3, 7, 21)
• Tuberculosis (upper lobe predominance)
• Modern, adequately-treated episodes in industrialized nations rarely cause bronchiectasis

2. Cystic Fibrosis (CF)

• Mutation of CFTR gene leads to defective chloride transport, thick mucus, and chronic infection
• Upper lobe predominance typical; S. aureus and P. aeruginosa are classic pathogens
• A separate disease entity but the prototype for understanding bronchiectasis mechanisms

3. Primary Ciliary Dyskinesia (PCD)

• Ultrastructural defects of cilia (usually absent dynein arms)
• Results in absent or dysfunctional mucociliary clearance
• Kartagener syndrome: situs inversus + bronchiectasis + sinusitis
• Nasal nitric oxide is markedly low; electron microscopy of cilia confirms diagnosis

4. Disorders of Immunity

• Common variable immunodeficiency (CVID): most common adult primary immunodeficiency causing bronchiectasis; low IgG, IgA, IgM; treat with IVIG
• X-linked agammaglobulinemia (Bruton's): low/absent B cells and all immunoglobulin classes
• IgA deficiency: most common primary immunodeficiency; recurrent sinopulmonary infections
• HIV infection

5. Allergic Bronchopulmonary Aspergillosis (ABPA)

• Hypersensitivity reaction to Aspergillus fumigatus in asthmatics or CF patients
• Causes central bronchiectasis (proximal, upper lobe) with mucoid impaction
• Diagnostic criteria (Murray & Nadel's, Table 69.2):
  • Predisposing condition: asthma or CF
  • Essential: Type I skin test (or elevated Aspergillus-specific IgE) AND total IgE >1000 IU/mL
  • Other (≥2 of 3): serum precipitins/IgG to Aspergillus; radiographic pulmonary opacities; eosinophil count >500 cells/μL

6. Nontuberculous Mycobacteria (NTM)

• Lady Windermere phenotype: bilateral right middle lobe and lingular bronchiectasis with nodular changes on CT
• Mycobacterium avium complex most common
• NTM can also colonize pre-existing bronchiectasis; dual role as cause and consequence

7. Connective Tissue Disorders

• Rheumatoid arthritis and Sjögren syndrome are the most commonly associated
• Also seen with ankylosing spondylitis and relapsing polychondritis

8. Alpha1-Antitrypsin Deficiency

• Reduced protease inhibitor activity allows neutrophil elastase to cause unchecked airway damage

9. Mounier-Kuhn Syndrome (Tracheobronchomegaly)

• Congenital absence/atrophy of tracheobronchial elastic and smooth muscle tissue
• Diagnosed by tracheobronchomegaly on CT (trachea >3 cm, main bronchi enlarged)

10. Williams-Campbell Syndrome

• Deficiency of bronchial cartilage distal to the first-generation bronchi
• Cystic bronchiectasis

11. Young Syndrome

• Obstructive azoospermia + chronic sinopulmonary infections
• Distinguishable from CF by normal sweat chloride; from PCD by normal ciliary ultrastructure

12. Postobstructive

• Bronchial stricture, endobronchial mass (carcinoid tumor), foreign body impaction
• Usually causes focal/unilateral bronchiectasis

13. Aspiration/Inhalation

• Recurrent aspiration: bilateral lower lobe predominance
• Toxic inhalation (ammonia, chlorine)

14. Idiopathic Bronchiectasis

• Accounts for 25-50% of cases after systematic evaluation
• Characteristic phenotype: bilateral lower lobe bronchiectasis + chronic rhinosinusitis
• HLA allelic polymorphisms (class I and II MHC) are statistically associated
• NK cell activation may play a role via killer cell Ig-like receptors (KIRs) recognizing HLA-C molecules on infected cells surfaces
• Murray & Nadel's, Ch. 69; Fishman's, Ch. 51

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Radiologic Distribution by Etiology

• Fishman's, Ch. 51; Murray & Nadel's, Ch. 69 (Fig. 69.5)

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Clinical Features

Symptoms

• Chronic productive cough (hallmark): mucopurulent sputum, often >30 mL/day
• Recurrent respiratory infections requiring antibiotics
• Dyspnea and reduced exercise tolerance
• Hemoptysis: ranges from blood-streaked sputum to massive hemoptysis (due to bronchial artery hypertrophy)
• Fever, weight loss, fatigue during exacerbations
• Rhinosinusitis is a common comorbidity

Physical Signs

• Coarse crackles (inspiratory, basal)
• Wheezing (especially if airflow obstruction present)
• Finger clubbing (in advanced disease)
• Signs of associated conditions (situs inversus in Kartagener, nasal polyps in CF)

Sputum Bacteriology

• Haemophilus influenzae (most common)
• Pseudomonas aeruginosa (most important; associated with worse prognosis, increased hospitalization, accelerated FEV1 decline)
• Staphylococcus aureus
• S. pneumoniae
• NTM (Mycobacterium avium complex)

Exacerbations

1. Cough
2. Sputum volume/consistency
3. Sputum purulence
4. Breathlessness/exercise tolerance
5. Fatigue/malaise
6. Hemoptysis ...plus clinician determination that a change in treatment is required

• Fishman's, Ch. 51

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Pulmonary Function Tests

• Obstructive pattern most common (reduced FEV1/FVC, reduced FEV1)
• Mixed obstructive-restrictive in advanced disease
• Airflow obstruction may be partially reversible with bronchodilators
• Progressive FEV1 decline is accelerated by chronic P. aeruginosa infection

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Diagnosis

Step 1: Suspect the Diagnosis

• Persistent productive cough with mucopurulent sputum
• Recurrent lower respiratory infections requiring antibiotics
• P. aeruginosa infection without known risk factors
• Never-smokers labeled as COPD with recurrent exacerbations
• Unexplained hemoptysis

Step 2: Confirm with HRCT

• Airway dilation: lumen diameter >1 to 1.5x the adjacent vessel ("signet-ring sign")
• Lack of bronchial tapering from central to peripheral
• Tram-track sign (bronchial wall thickening on chest X-ray)
• Bronchial wall thickening
• Mucoid impaction
• "Tree-in-bud" pattern (mucus-filled peripheral bronchioles)
• Cysts arising from bronchial wall
• Areas of consolidation

Fishman's Figure 51-1: Tram-track sign and signet-ring sign on HRCT

Step 3: Identify the Etiology (Fishman's Table 51-1)

• CBC with differential (eosinophilia? leukopenia?)
• Serum immunoglobulins (IgG, IgM, IgA)
• ABPA screen: total IgE, Aspergillus-specific IgE and IgG, Aspergillus skin test
• Sputum culture (bacterial)

• HRCT confirms diagnosis
• Spirometry (pre- and post-bronchodilator)
• Sweat chloride and/or CFTR gene mutation analysis (all children; adults <40 years; older adults with upper lobe disease, S. aureus in sputum, malabsorption, male infertility)
• Connective tissue disease serologies (ANA, RF, anti-Ro/La)
• HIV testing
• Sputum for AFB culture (NTM)
• Nasal nitric oxide (PCD screen - markedly low in PCD)
• Alpha1-antitrypsin level and phenotype
• Pneumococcal vaccine antibody response (to assess functional antibody production)

Identifying a specific etiology directly impacts treatment in up to 40% of patients

• Fishman's, Ch. 51

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Management

1. Airway Clearance Therapy (ACT)

• Chest physiotherapy (CPT) - postural drainage remains essential
• Active cycle of breathing techniques (ACBT)
• Oscillating positive expiratory pressure (OPEP) devices (Flutter, Acapella)
• Autogenic drainage
• Intrapulmonary percussive ventilation (IPV)
• Consider in all symptomatic patients with sputum production and/or frequent exacerbations
• Modality chosen should maximize patient adherence and minimize expense

• Hypertonic saline (7%): improves mucociliary clearance; evidence from RCTs in CF; used in non-CF bronchiectasis
• Mannitol (dry powder): osmotically rehydrates airway secretions

• Fishman's, Ch. 51

2. Antimicrobial Therapy

Exacerbation Treatment

• Oral antibiotics for mild-moderate exacerbations: based on sputum culture sensitivity
• IV antibiotics for severe exacerbations or failure of oral therapy
• H. influenzae: amoxicillin-clavulanate, quinolones
• P. aeruginosa: antipseudomonal beta-lactam ± aminoglycoside (often requires IV)
• Duration: typically 14 days

Long-Term Suppressive Therapy

• Inhaled tobramycin (TOBI)
• Inhaled aztreonam
• Inhaled colistin
• Rotating oral antibiotics

3. Anti-inflammatory Therapy - Macrolides

• Inhibit mucus hypersecretion
• Reduce IL-8 and neutrophil elastase
• Inhibit neutrophil adhesion to epithelial cells
• Reduce biofilm formation
• Inhibit production of reactive oxygen species
• Inhibit quorum sensing by P. aeruginosa

• Frequent exacerbations (>3/year)
• Normal ECG
• No significant cardiac disease

• Fishman's, Ch. 51

4. Inhaled Corticosteroids (ICS)

• Limited evidence for benefit in non-CF bronchiectasis
• May reduce sputum volume in patients with daily sputum production
• Not routinely recommended; may be considered in patients with coexisting asthma or ABPA

5. Bronchodilators

• Beta-2 agonists: improve mucociliary clearance and reverse bronchoconstriction
• Indicated when airflow obstruction documented
• Useful as adjunct to ACT

6. Treatment of ABPA (when underlying cause)

• Oral prednisolone: mainstay of treatment; reduces eosinophilic inflammation
• Itraconazole: antifungal; used as steroid-sparing agent
• Total IgE used to monitor disease activity

7. Surgery

• Localized disease not amenable to or failed medical therapy
• Massive/life-threatening hemoptysis (also consider bronchial artery embolization)
• Resection of destroyed/non-functional lobe (e.g., middle lobe syndrome)
• Surgery contraindicated in diffuse disease
• Lung transplantation: end-stage bronchiectasis with severe functional limitation

8. Management of Hemoptysis

• Mild-moderate: treat underlying infection; consider antifibrinolytics (tranexamic acid)
• Massive hemoptysis (>300 mL/24h): medical emergency
  • Airway protection
  • Bronchial artery embolization (BAE): procedure of choice for acute massive hemoptysis
  • Surgical resection if BAE fails or recurs

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Prognosis

• Chronic Pseudomonas aeruginosa infection (single most important prognostic factor)
• Larger sputum volume
• Severity of airflow obstruction (lower FEV1)
• Diffuse versus focal disease
• Presence of comorbidities (immunodeficiency, connective tissue disease)
• Frequent exacerbations (associated with accelerated FEV1 decline)

• Fishman's, Ch. 51; Murray & Nadel's, Ch. 69

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Key Points Summary (for 15-Mark Exam Answer)

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