Pulmonary · PANCE / PANRE

Cystic Fibrosis

Autosomal recessive CFTR dysfunction causing thick secretions, lung disease, and pancreatic insufficiency.

Also known as: CF, cystic fibrosis, CFTR, mucoviscidosis

Overview

Autosomal recessive multisystem disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7, leading to dysfunctional chloride and bicarbonate transport, thick viscous secretions, and progressive damage to lungs, pancreas, intestines, hepatobiliary tract, and reproductive system.

Epidemiology

Most common life-shortening autosomal recessive disease in white populations (~1:2500 live births); ~30,000 affected in the US. Median predicted survival in patients born now exceeds 50 years thanks to CFTR modulators and aggressive care.

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Question 1PulmonaryMedium
A 25-year-old woman with cystic fibrosis who is homozygous for the F508del mutation has an FEV1 of 65% predicted and frequent pulmonary exacerbations despite airway clearance and inhaled antibiotics. Which of the following CFTR modulator regimens is most appropriate?
  • ATezacaftor/ivacaftor dual therapy
  • BLumacaftor/ivacaftor dual therapy
  • CElexacaftor/tezacaftor/ivacaftor
  • DIvacaftor potentiator monotherapy
Reveal answer & full explanation
Correct answer: C — Elexacaftor/tezacaftor/ivacaftor
  • ATezacaftor/ivacaftor dual therapy
  • BLumacaftor/ivacaftor dual therapy
  • CElexacaftor/tezacaftor/ivacaftor
  • DIvacaftor potentiator monotherapy

Why Elexacaftor/tezacaftor/ivacaftor is correct

  • Elexacaftor/tezacaftor/ivacaftor (ETI) is the most effective CFTR modulator and is the standard of care for patients with at least one F508del allele, including F508del homozygotes
  • It pairs two correctors (elexacaftor, tezacaftor) with a potentiator (ivacaftor), improving CFTR protein folding, trafficking, and channel gating
  • In trials it raised FEV1 by roughly 14 percentage points, cut pulmonary exacerbations substantially, and lowered sweat chloride while improving BMI
  • It is appropriate for the great majority of people with CF, making it first-line modulator therapy here

Why the others are wrong

  • Tezacaftor/ivacaftor dual therapy — a dual corrector/potentiator approved for F508del homozygotes but less effective than triple therapy; right class, lesser drug (right-diagnosis-wrong-step)
  • Lumacaftor/ivacaftor dual therapy — an earlier dual modulator for F508del homozygotes with smaller FEV1 gains and more drug interactions and chest tightness than ETI (premature closure on an older agent)
  • Ivacaftor potentiator monotherapy — a potentiator effective only for gating mutations such as G551D, not for F508del homozygotes, who need a corrector (buzzword-matching "ivacaftor")
Question 2PulmonaryMedium
A 19-year-old woman with cystic fibrosis presents with worsening dyspnea, increased purulent sputum, and a 4 kg weight loss over 3 weeks. Sputum culture grows Pseudomonas aeruginosa. FEV1 has declined 18% from baseline. Which intravenous antibiotic regimen is most appropriate?
  • AIV tobramycin plus piperacillin-tazobactam
  • BIV ciprofloxacin plus vancomycin
  • CIV vancomycin plus cefepime
  • DIV azithromycin plus ceftriaxone
Reveal answer & full explanation
Correct answer: A — IV tobramycin plus piperacillin-tazobactam
  • AIV tobramycin plus piperacillin-tazobactam
  • BIV ciprofloxacin plus vancomycin
  • CIV vancomycin plus cefepime
  • DIV azithromycin plus ceftriaxone

Why IV tobramycin plus piperacillin-tazobactam is correct

  • Acute pulmonary exacerbations of cystic fibrosis (CF) due to Pseudomonas are treated with two anti-pseudomonal agents to broaden coverage and limit resistance
  • An aminoglycoside (tobramycin) plus an antipseudomonal beta-lactam (piperacillin-tazobactam, ceftazidime, or meropenem) is the standard combination

Why the others are wrong

  • B) IV ciprofloxacin plus vancomycin — vancomycin targets MRSA rather than Pseudomonas; oral ciprofloxacin monotherapy would be reserved for mild exacerbations and is inadequate for this degree of FEV1 decline and weight loss
  • C) IV vancomycin plus cefepime — vancomycin targets MRSA rather than Pseudomonas
  • D) IV azithromycin plus ceftriaxone — azithromycin provides only anti-inflammatory benefit in CF and is not exacerbation therapy; ceftriaxone lacks reliable anti-pseudomonal activity
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Risk factors

  • Caucasian (Northern European) ancestry — highest prevalence
  • Family history (autosomal recessive — both parents carriers)
  • F508del is the most common pathogenic CFTR mutation (~70% of US alleles)
  • Carrier frequency ~1:25 in white populations

Pathophysiology

CFTR is an apical membrane chloride/bicarbonate channel. Dysfunction → dehydrated, thick mucus that impairs mucociliary clearance (lungs), obstructs pancreatic ducts (exocrine insufficiency), intestinal lumen (meconium ileus, DIOS), biliary tree (focal biliary cirrhosis), and vas deferens (CBAVD with male infertility). Chronic airway infection (S. aureus early, Pseudomonas aeruginosa later, Burkholderia cepacia complex), neutrophilic inflammation, and bronchiectasis develop.

Clinical presentation

Symptoms

  • Neonatal: meconium ileus (10-20%), failure to thrive, prolonged jaundice
  • Pulmonary: chronic productive cough, recurrent pneumonia, sinusitis, nasal polyps, wheeze, exercise intolerance, hemoptysis, clubbing
  • GI: bulky greasy foul-smelling stools, malabsorption (fat-soluble vitamin deficiencies A, D, E, K), distal intestinal obstruction syndrome (DIOS) in adolescents/adults
  • Endocrine: cystic fibrosis-related diabetes (CFRD), osteopenia/osteoporosis
  • Reproductive: male infertility from congenital bilateral absence of vas deferens (CBAVD, ~98% of men)
  • Atypical/late presentations: idiopathic chronic pancreatitis, isolated bronchiectasis, male infertility

Signs / physical exam

  • Clubbing, salty taste of skin, nasal polyps, sinus tenderness
  • Coarse crackles, wheezes, increased AP diameter
  • Hepatomegaly, organomegaly, evidence of malnutrition
  • Rectal prolapse in young children

Differential diagnosis

  • Non-CF bronchiectasis — Negative sweat chloride and CFTR testing; alternative cause (immunodeficiency, PCD, NTM)
  • Primary ciliary dyskinesia (Kartagener) — Situs inversus, infertility, sinusitis, bronchiectasis; low nasal NO; abnormal ciliary biopsy
  • Immunodeficiency (CVID, hypogammaglobulinemia) — Low Ig levels, recurrent sinopulmonary infections, normal sweat chloride
  • Asthma — Reversible obstruction, atopy; no pancreatic involvement; normal sweat test
  • Shwachman-Diamond syndrome — Pancreatic insufficiency + cytopenias + skeletal abnormalities; ribosomal gene mutation; normal sweat chloride
  • Celiac disease — Failure to thrive, malabsorption with normal sweat chloride; positive tTG IgA, biopsy

Diagnostic workup

Diagnostic criteria

CF Foundation 2017: clinical features OR positive newborn screen OR sibling history PLUS evidence of CFTR dysfunction — sweat chloride ≥60 mmol/L (two tests) OR two disease-causing CFTR mutations OR abnormal nasal potential difference.

Labs

  • Sweat chloride test (pilocarpine iontophoresis) — diagnostic gold standard: ≥60 mmol/L on two occasions confirms CF; 30-59 intermediate; <30 normal
  • CFTR gene panel (>2000 mutations identified)
  • Newborn screening: immunoreactive trypsinogen (IRT) + CFTR mutation panel (now universal in US — diagnosis in infancy in most cases)
  • Pancreatic function: fecal elastase (<200 µg/g suggests insufficiency)
  • Sputum culture (S. aureus, H. influenzae early; Pseudomonas, Burkholderia, NTM, fungi later)
  • OGTT annually after age 10 for CFRD screening
  • Fat-soluble vitamins A, D, E, K levels; albumin, prealbumin

Imaging

  • HRCT chest — bronchiectasis (upper lobe predominant in CF), mucus plugging, air trapping
  • CXR — hyperinflation, peribronchial thickening, atelectasis
  • Abdominal imaging if DIOS or biliary disease

Other studies

  • Spirometry — obstructive pattern; FEV1 trajectory drives treatment intensity
  • DEXA for bone density
  • Audiometry if aminoglycoside therapy

Diagnostic algorithm

Sweat Chloride (mmol/L)Interpretation
<30CF unlikely
30-59Intermediate — pursue CFTR genetic testing
≥60Consistent with CF (confirm on 2 occasions)
Sweat chloride interpretation (CF Foundation 2017 diagnostic criteria).

Treatment

First-line

  • CFTR modulator therapy — disease-modifying, transformative:
  • Elexacaftor/tezacaftor/ivacaftor (Trikafta) — for ≥2 years with ≥1 F508del or other responsive mutation; >85% of patients now eligible
  • Ivacaftor — for gating mutations (G551D and others)
  • Tezacaftor/ivacaftor, lumacaftor/ivacaftor — earlier-generation combinations
  • Airway clearance daily: chest physiotherapy, high-frequency chest wall oscillation vest, PEP devices
  • Inhaled mucolytics: dornase alfa (Pulmozyme) — cleaves DNA in purulent secretions; hypertonic saline 7% BID
  • Inhaled bronchodilator (albuterol) before airway clearance
  • Inhaled antibiotics for chronic Pseudomonas: tobramycin or aztreonam — alternating 28-day cycles
  • Pancreatic enzyme replacement (pancrelipase) with all meals/snacks for pancreatic-insufficient patients
  • Fat-soluble vitamin supplementation (ADEK), high-calorie diet, nutritional support
  • Vaccinations: annual influenza, pneumococcal, COVID-19, RSV, varicella; routine childhood schedule

Second-line / adjunct

  • Pulmonary exacerbations: IV antibiotics tailored to sputum culture — typically antipseudomonal beta-lactam (cefepime, ceftazidime, piperacillin-tazobactam) + aminoglycoside (tobramycin) for 10-14 days
  • Chronic azithromycin 250-500 mg 3×/week — anti-inflammatory benefit even without infection
  • CFRD: insulin (oral hypoglycemics generally inadequate); maintain high-calorie diet
  • DIOS: hydration, polyethylene glycol; meglumine diatrizoate (Gastrografin) enema
  • Lung transplantation: bilateral, when FEV1 <30% predicted or rapid decline
  • Burkholderia cepacia complex isolation = relative contraindication to transplant at many centers

Complications

  • Recurrent pulmonary exacerbations with progressive lung function decline
  • Massive hemoptysis, pneumothorax
  • Cor pulmonale, respiratory failure
  • Cystic fibrosis-related diabetes (CFRD)
  • CF liver disease, focal biliary cirrhosis, portal hypertension
  • Distal intestinal obstruction syndrome (DIOS)
  • Osteopenia, infertility (especially male CBAVD), nephrolithiasis
  • Allergic bronchopulmonary aspergillosis (ABPA)

PANCE pearls

  • Sweat chloride ≥60 mmol/L on two occasions is diagnostic; with newborn screening, most US patients are diagnosed in infancy.
  • Elexacaftor/tezacaftor/ivacaftor (Trikafta) has dramatically changed CF prognosis — eligible for ~90% of patients with ≥1 F508del or responsive mutation.
  • Chronic Pseudomonas colonization marks a shift toward inhaled antibiotic suppression therapy (tobramycin or aztreonam cycles).
  • Burkholderia cepacia complex isolation is often a transplant contraindication and a poor prognostic marker.
  • CFRD requires insulin (NOT oral agents) and a high-calorie, unrestricted diet — distinct from type 1 or 2 diabetes management.

References

  • CF Foundation — Cystic Fibrosis Foundation Patient Registry Annual Data Report (2023)
  • Trikafta Trial — Elexacaftor-Tezacaftor-Ivacaftor for CF with a Single F508del Allele (Middleton et al., NEJM 2019)
  • CFF Diagnosis — Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation (Farrell et al., J Pediatr 2017)
  • CFF Care Guidelines — Cystic Fibrosis Pulmonary Guidelines: Chronic Medications (Mogayzel et al., Am J Respir Crit Care Med 2013)

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