Cystic fibrosis

At a glance

• Autosomal recessive disease from two disease-causing CFTR variants. Carrier frequency is about 1 in 25 in people of northern European ancestry.
• Defective chloride and bicarbonate transport gives thick secretions in the airways, pancreas, liver, gut and vas deferens. Respiratory failure is still the main cause of death.
• Australia now has more adults than children with CF. Most are diagnosed by newborn screening, but milder disease still turns up in adults.
• CFTR modulators changed the disease. Elexacaftor-tezacaftor-ivacaftor (ETI, Trikafta) and vanzacaftor-tezacaftor-deutivacaftor (Alyftrek) are both PBS-listed.
• Care sits with a specialist CF centre and its multidisciplinary team. Guidance: the Cystic Fibrosis Australia Standards of Care (living document, revised October 2026) and the ECFS 2023 to 2024 standards series.

Genetics and pathophysiology

• Over 2,000 CFTR variants are described. F508del is the commonest; about 90% of Australians with CF carry at least one copy.
• Variants are grouped by mechanism, which predicts modulator response:

Class	Defect	Example	Modulator
I	No protein (nonsense, frameshift)	G542X	None effective
II	Misfolding, little reaches the surface	F508del	Correctors plus potentiator (ETI, Alyftrek)
III	Gating	G551D	Potentiator alone works (ivacaftor)
IV	Reduced conductance	R117H	Potentiator
V	Reduced amount	Splice variants	Variable

• Classes I to III usually cause pancreatic insufficiency and more severe lung disease. Classes IV and V are often pancreatic sufficient and diagnosed later.
• In the airway, dehydrated mucus and impaired mucociliary clearance lead to chronic infection and neutrophilic inflammation, then bronchiectasis that is worst in the upper lobes.

Diagnosis

• Sweat chloride is the first test (ECFS 2023 and CFF 2017 diagnostic consensus):
  • 60 mmol/L or more: consistent with CF
  • 30 to 59: intermediate; do extended CFTR genotyping, then nasal potential difference or intestinal current measurement if still unclear
  • under 30: CF unlikely
• Diagnosis needs a clinical feature or positive newborn screen plus evidence of CFTR dysfunction (raised sweat chloride or two disease-causing variants in trans).
• CFTR-related disorder: a single-organ condition (congenital bilateral absence of the vas deferens, recurrent pancreatitis, disseminated bronchiectasis) with CFTR dysfunction that doesn't meet CF criteria.
• Adults reach the diagnosis through bronchiectasis work-up, nasal polyps, male infertility or recurrent pancreatitis (see bronchiectasis and chronic pancreatitis).
• Reproductive carrier screening for CF, spinal muscular atrophy and fragile X has been Medicare-funded since November 2023.

Pitfall: a normal sweat test doesn't exclude CF in someone already on a modulator, which lowers sweat chloride by around 40 mmol/L.

CFTR modulators

Drug	Who (PBS)	Dosing points
Elexacaftor-tezacaftor-ivacaftor (Trikafta)	Aged 2 or over with at least one responsive variant (expanded to rarer responsive variants from 1 July 2025)	Two combination tablets in the morning and ivacaftor 150 mg in the evening, with fat-containing food
Vanzacaftor-tezacaftor-deutivacaftor (Alyftrek)	Aged 6 or over with at least one responsive variant (from 1 February 2026)	Once daily with fat-containing food
Ivacaftor (Kalydeco)	Gating variants such as G551D	Twice daily

Both need sinopulmonary or gastrointestinal and nutritional disease before starting, initiation by a CF respiratory specialist at (or with) a CF centre, and only one subsidised modulator at a time (PBS Schedule, November 2026).

• ETI evidence: Middleton 2019 (one F508del plus a minimal function variant): ppFEV1 up 14.3 points, 63% fewer exacerbations and sweat chloride down about 42 mmol/L compared with placebo. BMI and quality of life also improved.
• SKYLINE 102 and 103 (2025): once-daily vanzacaftor was non-inferior to ETI for ppFEV1 and lowered sweat chloride further, with more patients reaching under 30 mmol/L.
• Liver: ETI and Alyftrek both carry an FDA boxed warning for drug-induced liver injury and liver failure (2026 labels). Check ALT, AST, ALP and bilirubin at baseline, monthly for 6 months, 3-monthly for the next 12 months, then at least yearly, and more often with known liver disease. Interrupt if ALT or AST is over 5x ULN, or over 3x ULN with bilirubin over 2x ULN, or with symptoms of liver injury. Not recommended in moderate hepatic impairment (Child-Pugh B) and not to be used in severe (Child-Pugh C).
• Other monitoring: rash, raised CK and mood or sleep change.
• Interactions: strong CYP3A inducers (rifampicin, carbamazepine, phenytoin, St John's wort) cut levels so far that they shouldn't be combined. Strong inhibitors (itraconazole, posaconazole, clarithromycin) and moderate ones (fluconazole, erythromycin) need a reduced dose, and the regimens differ by drug. ETI with a strong inhibitor: two morning tablets twice a week; with a moderate inhibitor, two tablets and ivacaftor 150 mg on alternate days, no evening dose. Alyftrek: one tablet once weekly with a strong inhibitor, every other day with a moderate one. Avoid grapefruit.
• Mental health: depression, anxiety, insomnia and "brain fog" have been reported. Ask at each review; ECFS 2024 covers dose reduction or interruption when adverse effects persist.
• Weight gain is now common. Some patients move from undernutrition to obesity, hypertension and dyslipidaemia, so the old high-fat, high-calorie advice needs revisiting.

Pitfall: modulators don't reverse established bronchiectasis or eradicate chronic Pseudomonas. Keep culturing sputum, which many patients can no longer expectorate; induced sputum or bronchoscopy may be needed.

Respiratory management

Daily treatment

• Airway clearance once or twice daily with a CF physiotherapist: active cycle of breathing, positive expiratory pressure, oscillating devices, autogenic drainage. Exercise helps but doesn't replace it.
• Mucoactives: dornase alfa (PBS-listed for CF) and hypertonic saline 6 to 7% after a bronchodilator. Mannitol dry powder is an alternative.
• SIMPLIFY (2023): in ETI-treated patients with relatively preserved lung function, stopping hypertonic saline or dornase alfa for 6 weeks was non-inferior for ppFEV1. Treatment burden can be reduced selectively, not across the board.
• Azithromycin 250 mg daily or 500 mg three times weekly for chronic Pseudomonas. Exclude non-tuberculous mycobacteria first.
• Inhaled antibiotics for chronic Pseudomonas: tobramycin (nebulised or dry powder, 28 days on and 28 off), aztreonam lysine or colistin.

Microbiology

Organism	What to know
Staphylococcus aureus and H. influenzae	Early colonisers; MRSA is associated with faster decline
Pseudomonas aeruginosa	Most common chronic adult pathogen. Mucoid strains are hard to clear. Eradicate the first isolate
Burkholderia cepacia complex	B. cenocepacia can cause cepacia syndrome; transmissible; transplant contraindication at many centres
Achromobacter, Stenotrophomonas	Multiresistant; significance varies
NTM (especially M. abscessus)	Culture at least yearly. M. abscessus spreads between patients and needs months of combination treatment
Aspergillus	Colonisation, bronchitis or ABPA

• Infection control: people with CF shouldn't meet each other. Keep at least 2 metres apart, use single rooms and masks, and segregate B. cepacia complex and M. abscessus.
• ABPA in CF: a clinical deterioration with total IgE over 1,000 IU/mL (CFF 2003; the 2024 ISHAM revision uses 500 IU/mL across conditions), Aspergillus sensitisation and new infiltrates or mucus plugging. Treat with prednisolone, with or without itraconazole (watch the modulator interaction).

Pulmonary exacerbations

• Increased cough and sputum, falling FEV1 (often 10% or more), weight loss, fatigue and new crackles. Fever is often absent.
• Mild: oral antibiotics guided by the last sputum culture (ciprofloxacin for Pseudomonas).
• Moderate to severe: IV two antipseudomonal agents from different classes, usually an antipseudomonal beta-lactam with once-daily tobramycin (levels AUC-based or trough under 1 mg/L, per local protocol), for 10 to 14 days. This is standard practice, although trials comparing one agent with two are inconclusive (Cochrane 2021). Many centres use hospital in the home.
• STOP2 (2021): early responders did as well with 10 days as 14, and slower responders gained nothing from extending to 21.
• Intensify airway clearance; check glucose, as exacerbations unmask CFRD.
• Target SpO2 88 to 92% if hypercapnic, as in respiratory failure.

Complications

Respiratory

• Haemoptysis: minor streaking with infection is common. Massive haemoptysis (240 mL or more in 24 hours, or recurrent large volumes): admit, stop hypertonic saline, NSAIDs and vigorous airway clearance, give IV antibiotics and tranexamic acid, and arrange bronchial artery embolisation.
• Pneumothorax: a secondary pneumothorax, so admit; most need a drain, certainly if large or symptomatic (see chest pain). Stop positive pressure airway clearance and NIV until it resolves.
• Respiratory failure and pulmonary hypertension in advanced disease.

Extrapulmonary screen

Problem	What to do
Pancreatic insufficiency	Faecal elastase; enzyme replacement with meals (lipase under 10,000 units/kg/day to avoid fibrosing colonopathy); vitamins A, D, E and K
CF-related diabetes	Annual OGTT from age 10; insulin is the treatment. HbA1c misses it
Distal intestinal obstruction syndrome	Right iliac fossa mass, colicky pain, vomiting. Oral osmotic laxatives or Gastrografin. Exclude appendicitis and intussusception
CF liver disease	LFTs and ultrasound; cirrhosis and portal hypertension in a minority
Bone disease	DXA from about age 8 to 10 (or now, in an adult never scanned), repeated every 1 to 5 years depending on result (see osteoporosis)
Colorectal cancer	Colonoscopy from age 40, every 5 years (CFF 2018); from 30 after transplant
Renal	Aminoglycoside nephrotoxicity, stones, CKD with age
Sinus disease	Nasal polyps and chronic rhinosinusitis; saline irrigation, steroids, surgery

• ECFS 2024 "planning for a longer life" adds cardiovascular risk, cancer screening and age-related problems to annual review.

Special situations

• Fertility: over 95% of men are infertile from absent vas deferens, but sperm retrieval with ICSI works. Women's fertility often improves on modulators, and unplanned pregnancies have risen.
• Contraception: lumacaftor-ivacaftor reduces hormonal contraceptive effect; ETI and Alyftrek don't. Hormonal contraceptives may contribute to modulator rash: if rash develops, consider stopping both, then restart the modulator alone first.
• Pregnancy: high risk (preterm birth, gestational diabetes, lung decline). Screen for pre-existing CFRD with a 75 g OGTT when planning pregnancy or once pregnant, unless normal in the past 6 months (ADA/CFF 2010), and plan close joint care with maternal-fetal medicine. Stopping a modulator can cause maternal decline, so continuing is usually favoured after discussion. Prenatal exposure can give a false-negative newborn screen.
• Transplant referral (CFF 2019 consensus, ISHLT 2021): refer at FEV1 under 30%; under 40% with BMI under 18, more than two exacerbations a year needing IV antibiotics, massive haemoptysis (ICU or embolisation) or pneumothorax; or under 50% with rapid decline (more than a 20% relative fall in 12 months). Refer regardless of FEV1 with a 6-minute walk under 400 m, hypoxaemia, hypercapnia (PaCO2 over 50 mmHg), pulmonary hypertension, or an exacerbation needing positive-pressure ventilation. Modulators have pushed many patients away from this threshold.
• Aboriginal and Torres Strait Islander people: CF is less common, but chronic wet cough is common. Don't let a CF diagnosis distract from, or be mistaken for, post-infective bronchiectasis.

Pitfalls

• Calling adult bronchiectasis "post-infective" without a sweat test when the pattern is upper lobe or there are nasal polyps or infertility.
• Prescribing rifampicin for TB or NTM, or carbamazepine, to someone on a modulator.
• Using HbA1c to exclude CFRD.
• Starting azithromycin without excluding NTM.
• Thrice-daily aminoglycoside dosing instead of once daily with level monitoring.
• Forgetting monthly LFTs in the first 6 months of ETI or Alyftrek.
• Assuming a well patient on ETI no longer needs sputum cultures, infection control or annual screening.