Bronchiectasis

Question 1

What is bronchiectasis?

Answer 1

• Chronic infection/inflammation –> if inflammation does not resolve there is airway wall remodeling via proteases –> floppy/dilated bronchi (irrev) –> fail to effectively clear secretions –> chronic airway infection, excessive bronchial secretions and chronic, productive cough
• Can be local or diffuse depending on cause

Question 2

5 Normal Host Innate Resp Defenses

Answer 2

1- Secreted Anti-Microbial Proteins- Lactoferrin, lysozyme, defensins, collectins, secretory IgA

2- Mucus Blanket (gel layer) - Contains mucins that bind pathogens then cleared by mucociliary elevator

3- Airway Surface Liquid Beneath Mucus Blanket (sol layer) - Reservoir of anti-microbial proteins, fluid layer allows normal mucociliary clearance

4- Synchronous Ciliary Activity - Clears mucus w/ bound pathogens

5- Alveolar Macrophages - Phagocytosis in airspace

Question 3

3 Symptoms that Differentiate Bronchiectasis from Other Obstructive Diseases

Answer 3

• Clubbing
• Nasal polyps, nasal inflammation
• Mid-inspiratory crackles

Question 4

10 General Causes of Bronchiectasis

Answer 4

LOCAL
1- Acute Broncho-pulmonary Infection - Pertussis, measles, staph aureus, Klebsiella, hemophilus, Tb, histoplasmosis

2- Bronchial Obstruction - Aspiration, neoplasms (adenoma or carcinoma), chronic obstructive lung disease (asthma, alpha-1-trypsin def, dilation/scars on top of path) adenopathy (Tb, sarcoidosis)

SYSTEMIC
3- Cilia Abnormality - Immotile Cilia Syndrome (w or w/o Kartagener’s), ciliary dyskinesia

4- Defect in Airway Surface Fluid - CF

5- Immunodeficiencies - IgA def, IgG def, chronic granulomatous disease or HIV

6- Anatomic Defects - Cartilage def, relapsing polychondritis, bronchomalacia, amyloidosis, pulmonary sequestration

7- Irritant Inhalation - ammonia, talc, smoke, detergents

8- Lung Transplant Rejection

9- Obliterative bronchiolitis

10- Allergic fungal response - ABPA (from Aspergillosis)

Question 5

Treatment (7)

Answer 5

• Airway Hygiene - reduce mucus obstruction
  
  • chest physical therapy, postural drainage, chest wall oscillator
• Bronchodilators - inc ciliary beat frequency and dec airway hyper-reactivity
• Abx
  
  • Used during acute infectious exacerbation
  • Many pts ultimately get infected w/ Pseudomonas (creates biofilm so hard to penetrate) but tobramycin and aztreonam used to slow progression (inhaled abx)
  • May alternate on and off to prevent resistance
• Mucolytics - hypertonic saline/osmotically active agents
• Vaccination - for flu and pneumococcus b/c inc risk
• Resp Support - later in disease may need BiPaP
• Transplant

Question 6

Pulmozyme

Answer 6

• recombinant human DNase to dec mucus viscosity in CF b/c mucus of CF has neg-charged DNA stuck in it

Question 7

5 Classes of CFTR Mutations

Answer 7

• I - premature STOP
• II - misfolds and targeted for degradation (includes common deltaF508 - over 70% cases)
• III - full length protein makes it to cell membrane but defective
• IV - full length protein makes it to cell membrane but defective
• V - reduced mRNA/reduced protein production; so CFTR exists but not enough (may have milder form - normal sweat tests; just pancreatitis, recurrent resp infections, no liver involvement)

Question 8

CFTR in Lungs

Answer 8

• Normally regulates other channels on apical membrane
• Mutation –> dec Cl- conductance and inc ENaC activity (normally regulates this) –> not enough airway surface liquid –> dec mucociliary clearance

Question 9

CFTR in Other Organs

Answer 9

• Less NaCl absorption in sweat ducts –> hypertonic sweat
• Dec bicarb secretion in pancreas (b/c CFTR is a Cl-bicarb channel) –> less alkaline pancreatic secretions –> pancreatic fibrosis and recurrent pancreatitis
• Malabsorption; dec fat and fat-soluble vitamin absorption
• Mucus plug in bowel - bowel obstruction (meconium ileus)
• Liver - hepatobiliary disease
• Infertility in men b/c CFTR needed for development an patency of vas deferens (congenital bilateral absence of vas deferens -CBAVD)

Question 10

How to dx CF

Answer 10

• Newborn screening for 40+ mutations
• 2 sweat Cl- tests (>60)
• 2 CF gene mutations
• Lack of Cl- on nasal pot diff meas

Question 11

How to dx Immotile Cilia Syndrome

Answer 11

• Dec saccharin in nasal mucosa
• lack of dynein arms on EM of nasal epithelium (see 9+2 structure w/ inner arms but not outer)
• abnormal radionuclide mucus clearance scan
• abnormal ciliary beat freq seen in in vitro cells

Question 12

Ivacafator & Lumacaftir/Ivacaftor

Answer 12

• Ivacaftor (CFTR potentiator) restores chloride conductance in G551D mutation; keep channel locked in open position (15%)
• Lumacaftir/Ivacaftor (corrector + potentiator) to correct deltaF508 mutation (most common); stabilizes mutant form to get it to cell surface