cystic fibrosis

SECTION 1: Learning Outcomes

• Understand how the basic defect in cystic fibrosis (CF) gives rise to the disease.

• Understand how CFTR modulators can be used to treat CF.

• Explore novel approaches in the treatment of CF.

SECTION 2: What is Cystic Fibrosis (CF)?

• Definition: A genetic disease that affects multiple organs (especially lungs and pancreas) by clogging them with thick, sticky mucus.

• Genetics:

  • Single gene disease caused by mutations in the CFTR gene on chromosome 7q31.2 - q31.3.

  • Autosomal recessive: Requires two copies of the mutated gene (one from each parent).

  • Carrier frequency: 1 in 25 people (4%) carries a faulty CFTR gene, usually asymptomatically.

• Epidemiology:

  • The most common lethal genetic disease in Caucasians of Northern European descent.

  • Incidence: 1 in 2,000 live births.

  • Affects >100,000 people worldwide and >10,000 people in the UK.

SECTION 3: Main Symptoms & Clinical Presentation

• Key Feature: Build-up of thick, sticky mucus in the lungs, digestive system, and other organs.

• Organ-Specific Manifestations:

  • ENT: Chronic sinusitis, nasal polyps.

  • Lungs: Cough with sputum, airflow obstruction, recurrent infections (especially Pseudomonas aeruginosa and Staphylococcus aureus).

  • GI Tract: Pancreatic insufficiency (malnutrition, fatty stools), pancreatitis, meconium ileus (in neonates), biliary cirrhosis.

  • Genitourinary & Reproductive: Male infertility (absent/obstructed vas deferens), female infertility, genitourinary problems.

  • Other: Digital clubbing, salty-tasting skin (salty sweat – a diagnostic sign).

SECTION 4: Pathophysiology – From Gene to Disease

• The CFTR Protein: The CFTR gene encodes the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a 1480-amino acid protein that functions as a chloride channel on epithelial cell surfaces.

• The Core Defect: Mutations lead to a dysfunctional CFTR protein, causing:

  1. Lack of Cl⁻ secretion into the airway surface liquid.

  2. Excessive Na⁺ absorption via the Epithelial Sodium Channel (ENaC), which CFTR normally regulates.

• Consequences in the Lung:

  • Normal: Proper height/composition of airway surface liquid layer; effective mucociliary clearance.

  • CF: Reduced airway surface liquid height; thick, sticky mucus; impaired mucociliary clearance. This leads to chronic infection, inflammation, and eventually bronchiectasis (permanent dilation and damage of airways).

(Visual Description: A diagram contrasts a normal airway and a CF airway. In the normal airway, the CFTR channel releases Cl⁻, and the ENaC channel absorbs Na⁺ in balance, maintaining a healthy mucus layer. In the CF airway, the CFTR channel is defective (shown as a broken channel), Cl⁻ secretion stops, and ENaC is overactive, absorbing too much Na⁺ and water. This dehydrates the mucus, making it thick and sticky, and cilia cannot beat effectively.)

SECTION 5: The ΔF508 Mutation & Mutation Classes

• Most Common Mutation: ΔF508 (F508del) – a deletion of three base pairs (CTT) coding for phenylalanine at position 508. Present in ~65% of patients.

• Consequence of ΔF508: The mutant CFTR protein misfolds and is degraded within the cell, failing to reach the plasma membrane. This is a Class 2 mutation (defective processing/trafficking).

• 6 Classes of CFTR Defects: Mutations are classified by their functional consequence on the CFTR protein:

  • Class 1: No protein synthesis (e.g., nonsense mutations).

  • Class 2: Defective protein processing/trafficking (e.g., ΔF508).

  • Class 3: Impaired channel gating (e.g., G551D).

  • Class 4: Decreased channel conductance.

  • Class 5: Reduced protein synthesis.

  • Class 6: Decreased protein stability at the membrane.

(Visual Description: A chart lists the 6 mutation classes with example mutations and a simple icon depicting the defect, e.g., a stop sign for Class 1, a protein trapped inside a cell for Class 2, a closed gate for Class 3.)

SECTION 6: Disease Progression & Prognosis

• Systemic Effects: The ion transport defect affects many exocrine glands, leading to pancreatic insufficiency (85%), male infertility (98%), female infertility (20%), gallstones, and salty sweat.

• Primary Cause of Morbidity/Mortality: Lung disease. Reduced clearance and persistent infections lead to bronchiectasis and respiratory failure.

• Life Expectancy: Has improved dramatically with advances in care.

  • 1970s: Adolescence.

  • 1999: 30 years.

  • 2016: Median predicted survival was ~47 years.

  • Today: Predicted to be >40 years for a newborn.

SECTION 7: General Treatment Goals & Supportive Therapies

• Goals: Prevent/control lung infections; loosen/remove mucus; prevent intestinal blockages; ensure adequate nutrition/hydration.

• Non-Pharmacological: Physiotherapy, pulmonary rehab, supplemental oxygen, lifestyle/nutrition, lung transplant.

• Supportive Pharmacological Therapies:

  • Antibiotics (for infections)

  • Bronchodilators

  • Mucolytics (e.g., Dornase alfa (DNAase), hypertonic saline, inhaled mannitol)

  • Immunomodulators

  • Pancreatic enzyme supplements

SECTION 8: CFTR Modulators – Targeted Therapies

• Concept: Drugs designed to correct the malfunctioning CFTR protein. They are mutation-specific.

• Coverage: ~90% of the UK CF population has mutations eligible for these drugs.

• The Five Licensed Modulators & Their Components:

  1. Kalydeco® (Ivacaftor) – CFTR Potentiator. Makes CFTR channels open longer. For gating mutations (Class 3), e.g., G551D.

  2. Orkambi® (Lumacaftor/Ivacaftor) – Corrector/Potentiator combo. For patients with two copies of F508del.

  3. Symdeko®/Symkevi® (Tezacaftor/Ivacaftor) – Corrector/Potentiator combo. For patients with two F508del or one F508del + one residual function mutation.

  4. Trikafta®/Kaftrio® (Elexacaftor/Tezacaftor/Ivacaftor) – Triple-combination corrector/potentiator. For patients with two F508del or one F508del + one minimal function mutation.

  5. Alyftrek® (Vanzacaftor/Tezacaftor/Deutivacaftor) – Next-gen corrector/corrector/potentiator combo. For patients ≥6 years with at least one F508del mutation (covers ~89% of people with CF in England).

(Visual Description: A diagram shows a cell with a misfolded CFTR protein (ΔF508) stuck in the endoplasmic reticulum. A "corrector" drug (like lumacaftor) helps it fold properly and traffic to the cell surface. At the membrane, a "potentiator" drug (like ivacaftor) helps the now-placed but often sluggish channel open more effectively.)

SECTION 9: Investigational Strategies for Non-Responsive Mutations

For the ~10% of patients with mutations not addressed by current modulators:

• Amplifiers (e.g., Nesolicaftor): Enhance CFTR protein production (for Class 5 mutations).

• Stabilizers (e.g., Cavosonstat): Stabilize CFTR protein at the cell membrane (for Class 6 mutations).

• Read-Through Agents (e.g., Ataluren): Induce ribosomes to "read through" premature stop codons (for Class 1b nonsense mutations).

• CFTR Bypass Strategies:

  • ENaC Blockers (e.g., VX-371): Inhibit the overactive sodium channel to rehydrate mucus.

  • Alternative Chloride Channel Activators (e.g., Denufosol): Activate other chloride channels (e.g., calcium-activated).

SECTION 10: Novel & Future Approaches

• Gene Editing (e.g., CRISPR/Cas9): Permanently correct the CFTR mutation at the DNA level within the patient's genome. Research is ongoing (e.g., at University College London) to develop an inhaled gene-editing treatment.

• Therapies at the RNA/Gene Level:

  • Gene Therapy: Delivery of normal CFTR cDNA via viral vectors (e.g., AAVs).

  • mRNA Replacement: Delivery of normal CFTR mRNA via lipid nanoparticles.

  • Antisense Oligonucleotides (ASOs): e.g., SPL84, which corrects specific splicing mutations (Class V) by causing the cell to "skip" a faulty part of the RNA.

• Stem Cell Therapy: Using induced pluripotent stem cells (iPSCs). Patient cells could be gene-edited ex vivo to correct the CFTR mutation, then differentiated into airway epithelial cells and reintroduced to regenerate healthy lung tissue.

(Visual Description: A conceptual figure shows four quadrants of novel approaches: 1) Viral/LNP delivery of CFTR cDNA/mRNA (top), 2) ASOs for splicing correction (left), 3) Suppressor tRNAs for nonsense mutations (bottom), 4) ASOs for polyadenylation issues (right).)

SECTION 11: NICE Guidance on Mucolytics

• First-line: Dornase alfa.

• Second-line/add-on: Dornase alfa plus hypertonic sodium chloride, or hypertonic saline alone.

• Alternative: Inhaled mannitol dry powder is recommended if dornase alfa is unsuitable or if lung function is declining rapidly

QUESTIONS:

Section 1: Single Best Answer Questions

Q1:

A patient with CF has two copies of the F508del mutation. Which class of CFTR defect does this represent?
A) Class 1 (no protein synthesis)
B) Class 2 (defective protein processing/trafficking)
C) Class 3 (impaired channel gating)
D) Class 4 (decreased channel conductance)

Answer:

B - Class 2 (defective protein processing/trafficking)
Rationale: The ΔF508 mutation causes misfolding of the CFTR protein, leading to its degradation in the endoplasmic reticulum before it reaches the cell membrane. This is the hallmark of Class 2 mutations.

Q2:

Which CFTR modulator combination is specifically indicated for a patient with a G551D mutation?
A) Kalydeco® (ivacaftor) alone
B) Orkambi® (lumacaftor/ivacaftor)
C) Symkevi® (tezacaftor/ivacaftor)
D) Kaftrio® (elexacaftor/tezacaftor/ivacaftor)

Answer:

A - Kalydeco® (ivacaftor) alone
Rationale: G551D is a Class 3 (gating) mutation. Ivacaftor is a potentiator that specifically helps defective channels open longer, and is approved as monotherapy for this mutation. Correctors are needed for ΔF508.

Q3:

In the pathophysiology of CF lung disease, what is the primary consequence of defective CFTR function?
A) Increased Cl⁻ secretion into airway surface liquid
B) Excessive Na⁺ absorption via ENaC
C) Reduced water secretion into the intestinal lumen
D) Increased mucin gene expression

Answer:

B - Excessive Na⁺ absorption via ENaC
Rationale: CFTR normally regulates ENaC. Without functional CFTR, ENaC becomes overactive, absorbing excess Na⁺ and water from airway surface liquid, dehydrating mucus. This is more immediate than the other listed effects.

Q4:

Which novel therapy approach uses antisense oligonucleotides to cause "exon skipping" to correct specific splicing mutations?
A) Gene editing (CRISPR/Cas9)
B) mRNA replacement via lipid nanoparticles
C) Read-through agents (e.g., ataluren)
D) Amplifiers (e.g., nesolicaftor)

Answer:

The question describes antisense oligonucleotides for splicing correction, which is a specific application of ASOs for Class V mutations. None of the options directly say ASOs, but among these, read-through agents are for nonsense mutations, amplifiers increase protein production, mRNA replacement delivers correct mRNA, and gene editing edits DNA. ASOs are a separate category not listed. Based on the notes, SPL84 is an ASO for splicing correction.

Answer (if ASO was an option): Antisense oligonucleotides (ASOs)
Since not an option: The description best matches an approach not listed, but among these, none directly correspond. Gene editing (A) is DNA-level; mRNA replacement (B) delivers new mRNA; read-through agents (C) are for nonsense mutations; amplifiers (D) increase protein production.

Clarification needed: The options don't include ASOs. The correct approach for splicing mutations is antisense oligonucleotides.

Section 2: Extended Matching Questions

Theme: CFTR Mutation Classes & Examples

Options:
A) Class 1 (no protein)
B) Class 2 (processing/trafficking)
C) Class 3 (gating)
D) Class 4 (conductance)
E) Class 5 (reduced synthesis)

Q1:

G551D mutation

Answer:

C - Gating mutation (channel doesn't open properly).

Q2:

Nonsense mutation (e.g., G542X)

Answer:

A - Premature stop codon → no full-length protein.

Q3)

ΔF508 (F508del) - most common

Answer:

B - Misfolding → degradation → doesn't reach membrane.

Q4)

Mutation reducing amount of normal CFTR produced

Answer:

E - Class 5 mutations affect promoter/splicing → less protein.

Theme: CFTR Modulator Mechanisms

Options:
A) Potentiator (helps channel open)
B) Corrector (helps protein fold/traffic)
C) Amplifier (increases protein production)
D) Stabilizer (keeps protein at membrane)
E) Read-through agent (bypasses stop codon)

Q1:

Ivacaftor component in Kalydeco®

Answer:

A - Potentiator increases channel open probability.

Q2:

Lumacaftor component in Orkambi®

Answer:

B - Corrector helps ΔF508 protein fold and reach membrane.

Q3)

Ataluren for nonsense mutations

Answer:

E - Induces ribosome to read through premature stop codons.

Q4)

Nesolicaftor (investigational)

Answer:

C - Amplifier increases CFTR mRNA translation → more protein.

Section 3: Clinical Scenario - Treatment Planning

Scenario: Emma, 12 years old, newly diagnosed with CF via newborn screening but only now symptomatic. Genetic testing shows F508del/G551D compound heterozygote. She has cough with sputum, Pseudomonas aeruginosa in sputum culture, and pancreatic insufficiency (steatorrhea). FEV1 85% predicted.

Q: Develop a comprehensive management plan including CFTR modulator selection, supportive therapies, and monitoring.

In-depth Answer:

GENETIC ANALYSIS & MODULATOR SELECTION:

• F508del: Class 2 (processing) → needs corrector

• G551D: Class 3 (gating) → needs potentiator

• Eligible for: Kaftrio® (elexacaftor/tezacaftor/ivacaftor) OR could consider Symkevi® (tezacaftor/ivacaftor) since one allele is gating

• Optimal choice: Kaftrio® triple therapy (elexacaftor/tezacaftor/ivacaftor)

  • Rationale: Addresses both mutations maximally

  • Elexacaftor: Next-gen corrector for F508del

  • Tezacaftor: Corrector for F508del

  • Ivacaftor: Potentiator for G551D

• Dosing: Based on weight (likely 2 tablets AM, 1 tablet PM)

• Expected benefits: Improved lung function (FEV1 increase 10-15%), reduced exacerbations, weight gain, better quality of life

SUPPORTIVE THERAPIES:

1. Airway Clearance:

• Physiotherapy: Twice daily (postural drainage, PEP mask)

• Mucolytic: Dornase alfa (Pulmozyme®) 2.5mg once daily via nebulizer

  • First-line per NICE, cleaves DNA in thick sputum

• Consider add-on: Hypertonic saline 7% if mucus remains thick

2. Infection Control:

• Pseudomonas eradication: Tobramycin inhalation solution 300mg BD for 28 days

• Chronic suppression: After eradication, consider cyclical tobramycin (28 days on/off)

• Monitoring: Monthly sputum cultures

3. Pancreatic Insufficiency:

• Pancreatic enzyme replacement therapy (PERT): Creon® capsules with all meals/snacks

• Dosing: Start 500-1000 lipase units/kg/meal, adjust based on symptoms/stool

• Fat-soluble vitamins: ADEK supplements (AquADEK® or similar)

• Nutrition: High-calorie, high-protein diet; consider overnight feeding if poor weight gain

4. Other:

• Exercise program: Daily aerobic activity

• Psychosocial: CF team support, school liaison

MONITORING PLAN:

Monthly:

• Weight, height (growth velocity)

• Sputum culture

• Symptom review

3-month (post-Kaftrio initiation):

• Spirometry (FEV1, FVC)

• Quality of life questionnaire (CFQ-R)

• Bloods: LFTs (monitor transaminitis), renal function

• Review adherence, side effects

6-month:

• CT chest (baseline for bronchiectasis)

• Oral glucose tolerance test (CF-related diabetes screening)

• Bone density (DEXA) baseline

• Vitamin levels (A, D, E, INR for K)

Annual:

• Full CF team review

• Hearing test (aminoglycoside monitoring)

• Eye exam (vitamin A toxicity)

EDUCATION FOR EMMA & FAMILY:

Medication timing:

• Kaftrio: Morning doses with fatty food (enhances absorption)

• Creon: With every meal/snack (don't chew/crush capsules)

• Dornase alfa: At least 1 hour before physio

• Tobramycin: Separate from dornase alfa by 1+ hour

Side effect monitoring:

• Kaftrio: Rash, elevated LFTs, cataracts (ophthalmology exam at baseline and annually)

• Creon: Abdominal pain, constipation (dose adjustment needed)

• Tobramycin: Tinnitus, dizziness (ototoxicity)

Sick day rules:

• Continue all medications unless vomiting

• Contact team for illness (may need IV antibiotics)

• Maintain hydration

TRANSITION PLANNING:

• Begin preparing for transition to adult services at age 14

• Encourage self-management skills

DOCUMENTATION:

• Mutation-specific therapy rationale

• Multidisciplinary care plan

• Response criteria for Kaftrio (FEV1 improvement, weight gain)

PROGNOSTIC DISCUSSION:

• With current therapies, life expectancy >40 years

• Goal: Preserve lung function >80% predicted through adolescence

• Fertility implications (future discussion)

Section 4: Novel Therapies & Future Directions

Scenario: A patient with CF has a nonsense mutation (Class 1b) not responsive to current modulators. His family asks about experimental therapies.

Q: Explain the investigational approaches for nonsense mutations, including mechanisms, stages of development, and practical considerations.

In-depth Answer:

PATHOPHYSIOLOGY OF NONSENSE MUTATIONS:

• Example: G542X, W1282X (premature stop codons)

• Effect: Ribosome stops translation → truncated, non-functional CFTR protein

• Class: 1b (nonsense-mediated decay may also reduce mRNA)

INVESTIGATIONAL APPROACHES:

1. Read-Through Agents (Small Molecules):

• Mechanism: Induce ribosome to "read through" premature stop codon by incorporating near-cognate tRNA

• Example: Ataluren (PTC124)

  • Development: Phase 3 trials showed mixed results; not approved for CF (approved for Duchenne muscular dystrophy)

  • Challenges: Efficiency varies by stop codon context, potential toxicity

• Next-gen: ELX-02 (similar mechanism, potentially higher efficacy)

2. Suppressor tRNAs (Gene Therapy):

• Mechanism: Deliver engineered tRNAs that recognize stop codons and insert amino acids

• Example: NTLA-5001 (in development)

• Advantage: Could work for any nonsense mutation at specific codon

• Challenge: Delivery to airway epithelium, potential off-target effects

3. Antisense Oligonucleotides (ASOs) to Promote Read-Through:

• Mechanism: ASOs bind near stop codon to alter RNA structure and facilitate read-through

• Example: SPL84-13 (for 3849+10kb C→T splicing mutation, not pure nonsense)

• Status: Early clinical trials

4. Gene Editing (CRISPR/Cas9):

• Mechanism: Direct correction of DNA sequence

• Approaches:

  • Direct correction: Change stop codon back to sense codon

  • Exon skipping: Remove exon containing stop codon (if in-frame)

• Example: UCL research on inhaled CRISPR for CF

• Challenges: Delivery efficiency, off-target edits, immune response

5. mRNA Replacement:

• Mechanism: Deliver corrected CFTR mRNA via lipid nanoparticles (LNPs)

• Example: Translate Bio/MRT5005 (phase 1/2 trial)

• Advantage: Bypasses DNA integration concerns

• Challenge: Repeated dosing needed (mRNA degrades), LNP delivery to lungs

6. Amplifiers + Read-Through Combination:

• Rationale: Increase CFTR production + promote read-through

• Example: Nesolicaftor (amplifier) + ataluren (read-through)

• Potential: Synergistic effect

CLINICAL TRIAL CONSIDERATIONS:

Eligibility:

• Age ≥18 years (mostly)

• FEV1 40-90% predicted

• No modulator eligible

• Specific nonsense mutation

Practical aspects:

• Frequency: Often daily oral or weekly inhaled

• Monitoring: Lung function, biomarkers (sweat chloride, nasal potential difference)

• Duration: 4-48 weeks in trials

RISKS & BENEFITS:

Potential benefits:

• Modest FEV1 improvement (3-5% in trials)

• Reduced exacerbations

• Improved quality of life

Risks:

• Drug-specific: e.g., renal toxicity with some read-through agents

• Procedure-related: Bronchoscopy for vector delivery

• Unknown long-term effects

ALTERNATIVE APPROACHES FOR SYMPTOM MANAGEMENT:

While awaiting mutation-specific therapy:

1. ENaC inhibitors: VX-371 (investigational) - reduces sodium absorption

2. Alternative chloride channel activators: Denufosol - activates TMEM16A

3. Anti-inflammatory: High-dose ibuprofen (slows lung function decline)

4. Aggressive supportive care: Optimize airway clearance, nutrition

PATIENT/FAMILY COUNSELING:

Realistic expectations:

• "These are early-stage therapies with modest effects"

• "Goal is to slow decline, not cure"

• "Most are 5-10 years from routine use"

Trial participation:

• Pros: Access to cutting-edge treatment, contribute to research

• Cons: Time commitment, uncertain benefit, potential side effects

Genetic counseling:

• Implications for family planning

• Sibling testing

• Carrier screening for partner

CURRENT STATUS FOR THIS PATIENT:

• Immediate: Optimize supportive care (dornase alfa, hypertonic saline, airway clearance)

• Intermediate: Consider clinical trial if available

• Long-term: Hope for gene editing/mRNA therapies

RESOURCES:

• Cystic Fibrosis Foundation (US) or Cystic Fibrosis Trust (UK) trial finder

• Specialist CF center with research program

• Patient advocacy groups for nonsense mutations

TAKE-HOME: While current modulators don't help nonsense mutations, multiple innovative approaches are in development. Participation in clinical trials offers the best chance for access while contributing to future treatments.

Section 5: Pediatric vs Adult CF Management

Scenario: Compare management considerations for:

• Patient A: 6-month-old diagnosed via newborn screening (ΔF508/ΔF508)

• Patient B: 35-year-old with advanced lung disease (FEV1 35%), CF-related diabetes, awaiting lung transplant

Q: Contrast monitoring, treatment priorities, and psychosocial aspects across these age extremes.

In-depth Answer:

PATIENT A (6-MONTH INFANT, ΔF508/ΔF508):

Early Intervention Goals:

1. Preserve lung function: Prevent initial infection/inflammation

2. Ensure nutrition: Support growth (weight/length percentiles)

3. Family education: Build daily care routines

Preventive Therapies:

• Airway clearance: Chest physiotherapy BID (parents perform)

• Nutrition: High-calorie formula, pancreatic enzymes with feeds, vitamin supplements

• CFTR modulator: Kaftrio® eligible from age 2+ (plan for early initiation)

• Infection prevention: RSV prophylaxis (palivizumab), flu vaccination for household

Monitoring:

• Weekly: Weight gain

• Monthly: Length, nutritional assessment

• Quarterly: CF clinic visit, sputum/oropharyngeal cultures

• Annual: Sweat test confirmation, baseline chest X-ray

Psychosocial:

• Parent support: Guilt, anxiety, care burden

• Sibling impact: Time allocation, genetic risk

• Financial: Medication costs, equipment

• Resources: Early intervention programs, parent support groups

PATIENT B (35-YEAR-OLD, ADVANCED DISEASE):

Management Priorities:

1. Symptom control: Dyspnea, cough, pain

2. Exacerbation prevention: Reduce hospitalizations

3. Comorbidity management: CF-related diabetes (CFRD), bone disease

4. Transplant evaluation: Timing, eligibility

Advanced Therapies:

• CFTR modulator: Likely on Kaftrio® if eligible

• Mucolytics: Dornase alfa + hypertonic saline + possibly mannitol

• Chronic antibiotics: Cyclical inhaled tobramycin/colistin, possibly chronic azithromycin

• Oxygen: For hypoxemia

• Non-invasive ventilation: For hypercapnic respiratory failure

• CFRD management: Insulin, dietary modification

Monitoring Intensity:

• Daily: Symptoms, blood glucose (if CFRD), oxygen saturation

• Weekly: Weight (fluid status)

• Monthly: Clinic visit, spirometry, bloods (renal, LFTs, glucose)

• 3-monthly: CT chest, bone density, diabetes review

Transplant Considerations:

• Referral criteria: FEV1 <30%, rapid decline, frequent exacerbations

• Evaluation: Psychosocial assessment, financial planning, support system

• Waitlist management: Maintain fitness, nutrition, infection control

Psychosocial Challenges:

• Employment: Disability, workplace accommodations

• Relationships: Dating disclosure, fertility issues (98% male infertility)

• Mental health: Depression/anxiety (30-40% prevalence)

• Advance care planning: End-of-life preferences

• Financial: Disability benefits, medication costs

COMPARATIVE TABLE:

TRANSITION CONSIDERATIONS:

• Pediatric to adult: Begins ~age 12, completes by 18

• Key elements: Self-care skills, understanding own health, navigating healthcare system

• Barriers: Parent letting go, adolescent risk-taking, gaps in care

END-OF-LIFE CARE (Adult Patient):

• Palliative integration: Early (not just terminal phase)

• Symptom management: Dyspnea, pain, anxiety

• Advance directives: Document preferences

• Family support: Grief counseling

HEALTHCARE TEAM COMPOSITION:

• Pediatric: Developmental specialist, play therapist, school liaison

• Adult: Transplant team, palliative care, vocational counselor

KEY MESSAGE: CF management evolves from preventive/parent-directed in infancy to complex self-management with palliative integration in adulthood. The goal shifts from preserving potential to optimizing quality of remaining life.