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); nearly 40,000 affected in the US. Median predicted survival for children born now exceeds 60 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?
AIvacaftor potentiator monotherapy
BTezacaftor/ivacaftor dual therapy
CLumacaftor/ivacaftor dual therapy
DElexacaftor/tezacaftor/ivacaftor
Reveal answer & full explanation
Correct answer: D — Elexacaftor/tezacaftor/ivacaftor
AIvacaftor potentiator monotherapy
BTezacaftor/ivacaftor dual therapy
CLumacaftor/ivacaftor dual therapy
DElexacaftor/tezacaftor/ivacaftor✓
Why Elexacaftor/tezacaftor/ivacaftor is correct
Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective triple CFTR modulator and 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 F508del homozygotes like this patient it added about 10 ppFEV1 points and lowered sweat chloride by about 45 mmol/L compared with tezacaftor/ivacaftor head to head (Heijerman, Lancet 2019)
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 — one corrector (tezacaftor) plus a potentiator, approved for F508del homozygotes but inferior to ETI head to head in this exact genotype; right class, lesser drug (the trap is the dated rule that homozygotes get dual therapy and triple therapy is only for heterozygotes)
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 indicated only for ivacaftor-responsive variants (gating variants such as G551D, plus residual-function variants such as R117H and certain splice variants); in F508del homozygotes the misfolded protein rarely reaches the cell surface, so a potentiator alone gives no meaningful benefit without correctors (buzzword-matching "ivacaftor")
Additional high-yield points
The often-quoted ~14-point ppFEV1 gain vs placebo (with a 63% lower pulmonary exacerbation rate) comes from F508del/minimal-function patients, not homozygotes (Middleton, NEJM 2019)
Vanzacaftor/tezacaftor/deutivacaftor (FDA approved December 2024) is a once-daily triple alternative for patients 6 and older with at least one F508del allele; it was noninferior to ETI on ppFEV1
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 ceftazidime plus meropenem
CIV vancomycin plus cefepime
DIV ciprofloxacin plus vancomycin
EIV azithromycin plus ceftriaxone
Reveal answer & full explanation
Correct answer: A — IV tobramycin plus piperacillin-tazobactam
AIV tobramycin plus piperacillin-tazobactam✓
BIV ceftazidime plus meropenem
CIV vancomycin plus cefepime
DIV ciprofloxacin plus vancomycin
EIV 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
IV ciprofloxacin plus vancomycin — ciprofloxacin covers Pseudomonas, but this regimen gives only one antipseudomonal agent, and vancomycin adds MRSA coverage that this culture does not call for; a moderate-to-severe exacerbation like this one (FEV1 decline, weight loss) is treated with an antipseudomonal beta-lactam plus an aminoglycoside
IV vancomycin plus cefepime — cefepime is an antipseudomonal beta-lactam, but pairing it with vancomycin gives only one antipseudomonal agent plus MRSA coverage that is not indicated here; Pseudomonas exacerbations are treated with two antipseudomonal classes (beta-lactam plus aminoglycoside)
IV azithromycin plus ceftriaxone — azithromycin provides only anti-inflammatory benefit in CF and is not exacerbation therapy; ceftriaxone lacks reliable anti-pseudomonal activity
IV ceftazidime plus meropenem — both drugs are antipseudomonal, so this looks like double coverage, but they are two beta-lactams sharing one mechanism of action; Pseudomonas exacerbations are treated with two different classes, an antipseudomonal beta-lactam plus an aminoglycoside.
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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)
Elexacaftor/tezacaftor/ivacaftor (Trikafta) — for ≥2 years with ≥1 F508del or other responsive mutation; >85% of patients now eligible; vanzacaftor/tezacaftor/deutivacaftor (Alyftrek, FDA 2024) is a once-daily triple alternative for ≥6 years with ≥1 F508del or other responsive mutation
Ivacaftor — for gating mutations (G551D and others)
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
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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