309.1 🎓 醫孞生版

309.1.0.1 📌 䞀頁重點

309.1.0.1.1 Definition + Epidemiology
309.1.0.1.1.1 Cystic Fibrosis (CF)
  • Autosomal recessive disorder
  • CFTR gene (chr 7q31) mutation
  • Affects chloride + bicarbonate transport
  • Multi-organ disease (lung + pancreas + GI + liver + sweat + reproductive)
309.1.0.1.1.2 Epidemiology
  • 1 in 2,500-3,500 live births in Caucasians
  • Less common in Asians, African Americans, Hispanics
  • ~ 30,000+ patients in US, 90,000+ globally
  • Taiwan: rare (~ 1 in 30,000-100,000)
  • Median survival 50+ in US (modern era)
  • Expected to reach 60+ for newborns with modern therapy
309.1.0.1.2 Pathophysiology
309.1.0.1.2.1 CFTR Function
  • Apical membrane chloride channel
  • Regulates Cl- + HCO3- transport
  • Indirectly affects Na+ + water transport
  • Critical for hydration of airway surface liquid
309.1.0.1.2.2 CFTR Dysfunction Consequences
  • Lungs: thick mucus + impaired mucociliary clearance + infection (Pseudomonas, S. aureus, NTM)
  • Pancreas: ductal obstruction + exocrine insufficiency + CFRD (CF-related diabetes)
  • Intestine: meconium ileus (newborn), DIOS (distal intestinal obstruction syndrome)
  • Liver: bile duct obstruction → cirrhosis
  • Sweat: ↑ Na+, Cl- (no resorption)
  • Reproductive: CBAVD (congenital bilateral absence of vas deferens) — male infertility
309.1.0.1.2.3 CFTR Mutation Classes
Class Defect Examples Severity
I No protein (premature stop) G542X, W1282X Severe
II Misfolded, degraded F508del (most common) Severe
III Defective gating G551D Severe
IV Reduced conductance R117H Mild
V Reduced quantity A455E Mild
VI Reduced stability rescued F508del Variable
309.1.0.1.3 Clinical Manifestations
309.1.0.1.3.1 Respiratory (Primary Cause of Morbidity/Mortality)
  • Chronic productive cough
  • Recurrent pulmonary infections
  • Bronchiectasis (universal in adults)
  • Wheeze, dyspnea
  • Hemoptysis
  • Pneumothorax (~ 20% lifetime)
  • Cor pulmonale (advanced)
  • ABPA (~ 10%)

Pathogens (Age-Dependent): - Pediatric early: S. aureus, H. influenzae - Pediatric/adolescent: P. aeruginosa - Adult: P. aeruginosa (chronic), B. cepacia complex (worst), NTM (MAC, M. abscessus), Aspergillus (ABPA) - Stenotrophomonas maltophilia, Achromobacter (emerging)

309.1.0.1.3.2 Pancreatic
  • Exocrine insufficiency (85-90% of patients)
    • Steatorrhea, weight loss, vitamin deficiency (A, D, E, K)
    • Pancreatic enzyme replacement therapy (PERT)
  • CFRD (CF-related diabetes)
    • 20-30% by adolescence, 40-50% by adulthood
    • Combined insulin deficiency + insulin resistance
    • HbA1c misleading (rapid turnover)
    • Continuous glucose monitoring (CGM)
    • Insulin treatment
309.1.0.1.3.3 Gastrointestinal
  • Meconium ileus (newborn, 15-20%)
  • DIOS (distal intestinal obstruction syndrome) in older
  • Constipation
  • GERD
  • Pancreatitis (with some CFTR mutations)
  • Rectal prolapse
309.1.0.1.3.4 Hepatobiliary
  • CFLD (CF-related liver disease):
    • Focal biliary cirrhosis → multilobular cirrhosis (10%)
    • Cholelithiasis, cholestasis
    • Liver transplant if portal HTN + decompensated
309.1.0.1.3.5 Sinus / Upper Airway
  • Chronic rhinosinusitis (universal)
  • Nasal polyposis (10-50%)
309.1.0.1.3.6 Sweat
  • Sweat chloride > 60 mmol/L = diagnostic (pilocarpine iontophoresis)
309.1.0.1.3.7 Reproductive
  • Males: CBAVD → infertility (98%)
  • Females: reduced fertility (thick cervical mucus), but pregnancies possible
  • IVF / ICSI for males
  • Pregnancy outcome improved with modern CFTR modulators
309.1.0.1.3.8 Other
  • Osteoporosis (multi-factorial)
  • Vitamin K deficiency → coagulopathy
  • Salt depletion → hyponatremic dehydration (esp infants in hot climates)
309.1.0.1.4 Diagnosis
309.1.0.1.4.1 Screening
  • Newborn screening (IRT — immunoreactive trypsinogen): standard in many countries; ↑ IRT → CFTR testing
  • CFTR genetic testing: targeted panel (most common mutations) or full sequencing
  • Sweat chloride test (pilocarpine iontophoresis) — gold standard if ≥ 60 mmol/L
309.1.0.1.4.2 Diagnostic Criteria (CFF + ECFS)
  • Clinical features (lung + pancreatic + GI + reproductive + family hx) PLUS
  • Evidence of CFTR dysfunction:
    • Sweat chloride ≥ 60 mmol/L OR
    • Two pathogenic CFTR mutations OR
    • Abnormal nasal potential difference (NPD)
309.1.0.1.4.3 CRMS / CF-SPID
  • CRMS: CF screen-positive inconclusive diagnosis
  • CF-SPID: equivalent
  • Monitor over time; some develop CF features
309.1.0.1.5 Treatment — Revolutionary CFTR Modulators
309.1.0.1.5.1 Ivacaftor (Kalydeco, 2012)
  • CFTR potentiator (improves gating)
  • For Class III mutations (G551D) and select others
  • Game-changer for ~ 5% of CF patients
309.1.0.1.5.2 Lumacaftor + Ivacaftor (Orkambi, 2015)
  • CFTR corrector + potentiator
  • For F508del homozygous
  • Modest benefit
309.1.0.1.5.3 Tezacaftor + Ivacaftor (Symdeko, 2018)
  • Improved corrector
  • F508del homozygous + select compound heterozygous
309.1.0.1.5.4 Elexacaftor + Tezacaftor + Ivacaftor (ETI, Trikafta in US, Kaftrio in Europe, 2019)
  • Triple combination
  • For F508del homozygous AND heterozygous + many other mutations
  • Game-changer: massive improvement in lung function, exacerbations, weight, QOL
  • Effective for ~ 90% of CF patients
  • 2023-2024 expanded indications (younger ages, more mutations)
309.1.0.1.5.5 Future Therapies
  • mRNA therapy
  • Gene therapy (viral or non-viral delivery)
  • CRISPR-based corrections
  • Patient-derived organoid testing for personalized response
309.1.0.1.6 Comprehensive Treatment
309.1.0.1.6.1 Airway Clearance
  • Chest physiotherapy + postural drainage
  • OPEP devices (Acapella, Flutter)
  • High-frequency chest wall oscillation (HFCWO vest)
  • Hypertonic saline (7% NaCl) nebulized — BID
  • Dornase alfa (rhDNase, Pulmozyme) — daily nebulized
  • Mannitol (less common)
309.1.0.1.6.2 Antibiotics

Acute Exacerbations: - IV antibiotics based on sputum cultures - Pseudomonas: combination (β-lactam + aminoglycoside) - 2-3 weeks typical

Chronic Suppressive: - Inhaled tobramycin (TOBI, Bethkis) — alternate months - Inhaled aztreonam (Cayston) — alternate months - Inhaled colistin - Azithromycin chronic 250-500 mg 3x/week

MRSA / MSSA: - Cefazolin / vancomycin / linezolid

B. cepacia complex: - Multi-drug resistant; difficult to treat - Excluded from many transplant centers - ↑ Mortality

NTM: - MAC, M. abscessus increasing - Long-term multi-drug therapy - Specialty referral

Antifungals (ABPA): - Itraconazole or voriconazole - Plus corticosteroids

309.1.0.1.6.3 Nutrition + Pancreatic
  • High-calorie + high-fat diet
  • PERT (pancreatic enzyme replacement): with all meals + snacks (lipase, amylase, protease)
  • Fat-soluble vitamin supplementation (A, D, E, K)
  • Salt supplementation (esp infants, hot weather)
  • CFRD management: insulin, CGM
  • Nutrition specialist
309.1.0.1.6.4 Other
  • Vaccinations (flu, pneumococcal, COVID, RSV, hepatitis)
  • Mental health support (depression common)
  • CF center referral (multidisciplinary care improves outcomes)
309.1.0.1.6.5 Transplantation
  • Lung transplant: for end-stage lung disease
    • FEV1 < 30% predicted + worsening
    • Refractory hypoxemia / hypercapnia
    • Massive hemoptysis
    • B. cepacia complex may be exclusion
  • Liver transplant: for decompensated cirrhosis (rare)
309.1.0.1.6.6 Pregnancy in CF
  • More common with modern therapy
  • High-risk: maternal lung function + nutrition + CFRD
  • ETI safe in pregnancy (limited data, growing evidence)
  • Preconception planning
  • IVF / ICSI for male infertility (CBAVD)
309.1.0.1.7 CFTR Modulator Eligibility (2024)
309.1.0.1.7.1 ETI (Trikafta/Kaftrio)
  • F508del homozygous
  • F508del heterozygous + virtually any other CFTR mutation
  • Expanded to ages 2 + (Europe), 6+ (US)
  • Continued expansion
309.1.0.1.7.2 Ivacaftor alone
  • For specific gating mutations (G551D class III + select)
  • Approved for younger ages
309.1.0.1.7.3 Lumacaftor / Tezacaftor (older)
  • Less effective than ETI
  • Mostly replaced
309.1.0.1.8 Outcomes
309.1.0.1.8.1 Survival
  • Pre-modulator era: median survival 30s
  • Post-modulator era: expected ≥ 60 for newborns
  • Adult CF patients > pediatric now
309.1.0.1.8.2 Quality of Life
  • Massive improvement with ETI
  • Pulmonary exacerbations reduced ~ 60%
  • Lung function improved
  • Weight gain
  • Subjective well-being

309.1.0.2 🩺 床邊速查

  • CF: autosomal recessive, CFTR mutation; F508del most common (70% Caucasian alleles)
  • Multi-organ: lung, pancreas (exocrine + DM), GI, liver, sweat, reproductive (CBAVD male infertility)
  • Diagnosis: sweat chloride ≥ 60 + clinical + genetic
  • CFTR modulators (revolutionary): ETI (Trikafta/Kaftrio) for F508del-containing genotypes; ivacaftor for G551D-class
  • Lung pathogens: pediatric S. aureus + H. influenzae → adolescent/adult Pseudomonas → late B. cepacia + NTM
  • CFRD: 20-30% adolescent, 40-50% adult; insulin therapy
  • Modern survival: ≥ 60 for newborns (vs 30s pre-modulator)