Cystic Fibrosis

Cystic fibrosis (CF) is a multisystem autosomal recessive disorder caused by pathogenic variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene located on chromosome 7q31.2. The defective CFTR protein impairs epithelial chloride and bicarbonate transport, leading to dehydrated, viscous secretions in the lungs, pancreas, hepatobiliary system, gastrointestinal tract, and reproductive tract.

CF is the most common life-limiting genetic condition among Australians of European descent. The Australian Cystic Fibrosis Data Registry (ACFDR), maintained by Cystic Fibrosis Australia, records approximately 3,500 people living with CF nationally. Carrier frequency is approximately 1 in 25 in populations of Northern European ancestry.

Since the introduction of universal newborn screening across all Australian jurisdictions (completed 2018), the majority of CF diagnoses are now made in the first 4–6 weeks of life, enabling early intervention and improved long-term outcomes. The establishment of accredited CF centres at major tertiary hospitals in each state and territory ensures multidisciplinary care delivery aligned with Cystic Fibrosis Australia standards.

Newborn Screening (NBS)

Universal newborn bloodspot screening is performed in all Australian states and territories. Most jurisdictions use an IRT–DNA or IRT–IRT–DNA algorithm:

• Step 1: Immunoreactive trypsinogen (IRT) measured on day 2–4 heel-prick bloodspot; elevated IRT (typically >99th percentile) triggers further testing.
• Step 2: CFTR mutation panel analysis (varies by state; typically 20–50 common mutations including F508del, G551D, G542X, etc.). Some states use a second IRT at 2–4 weeks before DNA analysis.
• Step 3: Referral to a paediatric CF centre for confirmatory sweat chloride testing within the first 4–8 weeks of life.

Sweat Chloride Testing

The sweat chloride test (pilocarpine iontophoresis) remains the gold standard for CF diagnosis. It must be performed in an accredited laboratory following the Gibson–Cooke or Macroduct methodology (CLSI C34-A3).

CFTR Mutation Analysis

Comprehensive CFTR genotyping is recommended for all individuals with a positive NBS, intermediate sweat chloride, or clinical features suggestive of CF. Next-generation sequencing (NGS) panels covering all 27 exons and splice sites are available at Australian genetic pathology laboratories (MBS item 73291 and related).

CFTR mutations are classified into six functional classes:

Pancreatic Status Assessment

Faecal elastase-1 (FE-1) is the preferred non-invasive test for pancreatic exocrine function:

• > 200 µg/g: Pancreatic sufficient (PS) — ~15% of CF patients
• 100–200 µg/g: Mildly insufficient — monitor closely
• < 100 µg/g: Pancreatic insufficient (PI) — requires PERT (~85% of CF patients)

CFTR modulators target the underlying protein defect rather than symptoms alone. They are classified as potentiators (improve gating of CFTR at the cell surface), correctors (improve folding and trafficking of CFTR to the cell surface), and amplifiers (increase CFTR mRNA). The availability of elexacaftor/tezacaftor/ivacaftor on the Australian PBS has been the single greatest advance in CF therapeutics.

Genotype–Modulator Matching Summary

Pulmonary disease accounts for the majority of CF morbidity and mortality. The objectives of pulmonary management are to clear airway secretions, prevent and treat lung infections, reduce inflammation, and maintain lung function. All pulmonary management should be guided by an accredited CF physiotherapist and respiratory physician.

Airway Clearance Techniques (ACTs)

Daily airway clearance is the cornerstone of CF lung care. The specific regimen should be individualised by a CF physiotherapist based on age, disease severity, patient preference, and sputum characteristics.

Inhaled Mucolytic Therapies

Inhaled Antibiotics — Maintenance

Inhaled Bronchodilators

Short-acting β₂-agonists (salbutamol 200–400 µg MDI via spacer or 2.5–5 mg nebulised) should be administered before airway clearance and hypertonic saline. Long-acting bronchodilators (salmeterol, formoterol) may be added for patients with documented bronchospasm or reversible obstruction on spirometry.

Inhaled Corticosteroids

Inhaled corticosteroids (ICS) are not routinely recommended for all CF patients. They should be considered only when there is a clear comorbid asthma or CF-associated allergic bronchopulmonary aspergillosis (ABPA). Unnecessary ICS use may increase the risk of NTM infection and adrenal suppression. If used, the lowest effective dose should be prescribed with regular reassessment.

Routine Pulmonary Monitoring

Lung infection is the primary driver of morbidity and mortality in CF. The microbiology of the CF airway evolves over time, with characteristic pathogens at different life stages. Eradication of initial infection and aggressive treatment of pulmonary exacerbations are fundamental to preserving lung function.

Typical Microbial Progression

Pseudomonas aeruginosa Eradication Protocol

Standard Australian eradication regimen (eTG-aligned):

• Oral ciprofloxacin 20–30 mg/kg/day (max 1.5 g/day) in two divided doses for 2–3 weeks PLUS
• Inhaled tobramycin 300 mg nebulised every 12 hours for 4 weeks (TOBI®) OR
• Inhaled colistimethate 1–2 million units every 12 hours for 4 weeks as alternative to tobramycin
• Follow-up sputum culture at 1 month after completion; if still positive, consider IV anti-pseudomonal therapy (see below)

Chronic Pseudomonas — Suppressive Therapy

Patients with chronic P. aeruginosa infection (defined as ≥3 positive cultures in the preceding 12 months, or persistently positive for >6 months) should receive continuous alternating inhaled antibiotic therapy:

• Month 1: Inhaled tobramycin 300 mg every 12 hours
• Month 2: Inhaled colistimethate 1–2 million units every 12 hours OR inhaled aztreonam 75 mg TDS
• Alternate monthly; continue indefinitely unless eradicated (rare in chronic infection)

Pulmonary Exacerbations — IV Antibiotic Therapy

Indications for IV antibiotics include declining FEV₁ (>10% from baseline), increased sputum volume/purulence, systemic symptoms (fever, weight loss, reduced appetite), or failure of oral/inhaled therapy. IV therapy is typically administered for 14 days, often as an inpatient or via Hospital in the Home (HITH).

Methicillin-Resistant Staphylococcus aureus (MRSA)

CA-MRSA prevalence in Australian CF populations is increasing, particularly in Northern Territory and remote communities. Eradication should be attempted on first isolation:

• Nasal mupirocin 2% ointment BD to each nostril for 5 days + chlorhexidine body washes daily for 5 days
• Consider adding oral TMP-SMX 160/800 mg BD or oral rifampicin 300 mg BD + fusidic acid 500 mg TDS for 2–4 weeks if persistent colonisation
• Chronic MRSA infection: suppressive therapy with TMP-SMX or linezolid (monitor FBC); vancomycin IV for exacerbations

Non-Tuberculous Mycobacteria (NTM)

Mycobacterium abscessus complex is the most clinically significant NTM in CF. It is associated with accelerated lung function decline and can be a relative contraindication to lung transplant at some centres. M. avium complex (MAC) also occurs. Diagnosis requires:

• Positive mycobacterial sputum culture (≥2 positive cultures, or 1 positive with CT findings suggestive of NTM) per ATS/IDSA criteria
• Speciation to species/ subspecies level (e.g., M. abscessus subsp. abscessus vs massiliense) — critical for treatment decisions
• Referral to specialist NTM service (Royal Melbourne Hospital, Westmead Hospital, Royal Adelaide Hospital, Sir Charles Gairdner Hospital have expertise)

Allergic Bronchopulmonary Aspergillosis (ABPA)

ABPA occurs in 2–9% of CF patients and presents with worsening asthma symptoms, fleeting pulmonary infiltrates, elevated total IgE (>500 IU/mL, typically >1,000), positive Aspergillus-specific IgE/IgG, and eosinophilia. Treatment:

• First-line: Oral prednisolone 0.5–1 mg/kg/day (max 40–60 mg) for 1–2 weeks, then taper over 2–3 months
• Steroid-sparing / steroid-refractory: Itraconazole 200 mg PO BD (monitor levels, CYP interactions) or voriconazole 200 mg PO BD
• Biologic therapy: Omalizumab (Xolair®) is increasingly used for refractory ABPA (PBS Authority Required, under specialist supervision)

Pancreatic Exocrine Insufficiency

Approximately 85% of CF patients have pancreatic insufficiency (PI), diagnosed by faecal elastase-1 <100 µg/g. Untreated PI leads to fat malabsorption, steatorrhoea, fat-soluble vitamin deficiency, failure to thrive, and distal intestinal obstruction syndrome (DIOS).

Distal Intestinal Obstruction Syndrome (DIOS)

DIOS results from inspissated faecal material in the ileocaecal region, presenting with crampy abdominal pain, palpable right iliac fossa mass, and constipation. Risk factors include PI, dehydration, immobility, and CFTR modulator initiation (may paradoxically alter stool consistency).

• Mild DIOS: Oral polyethylene glycol (PEG/Movicol®) 1–2 sachets BD; increase PERT dose; encourage fluids
• Moderate–severe DIOS: Gastrografin® (diatrizoate meglumine) 50–100 mL PO/NG diluted 1:1 with water; or balanced PEG-electrolyte solution via NG tube; IV fluids if dehydrated
• Refractory: Surgical consultation — differentiate from meconium ileus equivalent, intussusception, or distal intestinal tumour

Fat-Soluble Vitamins

CF-Related Diabetes (CFRD)

CFRD affects approximately 20% of adolescents and up to 50% of adults with CF. It results from progressive pancreatic fibrosis and insulin deficiency, compounded by CFTR-related β-cell dysfunction. CFRD is associated with accelerated decline in lung function, worse nutritional status, and increased mortality.

Treatment of CFRD:

• Insulin is the primary therapy — there is no role for sulfonylureas or metformin in CFRD
• Basal–bolus insulin regimen (e.g., insulin glargine once daily + insulin aspart with meals) is the standard approach
• CF patients require higher caloric intake — do NOT restrict carbohydrates; dose insulin to cover nutritional needs
• Continuous glucose monitoring (CGM) is increasingly used (FreeStyle Libre® — PBS-listed for diabetes in some contexts)
• Refer to endocrinologist with CF experience; collaborative CF-endocrine clinics exist at major CF centres

CF-Related Liver Disease

Hepatobiliary disease affects 2–40% of CF patients depending on definition. It ranges from neonatal cholestasis and hepatic steatosis to focal biliary cirrhosis and multilobular cirrhosis.

• Ursodeoxycholic acid (UDCA) 10–20 mg/kg/day in 2–3 divided doses is recommended for patients with evidence of CF-associated hepatopathy (elevated GGT, abnormal ultrasound) — PBS-listed for CF liver disease
• Annual liver function tests (LFTs) and liver ultrasound every 2–3 years from age 3 years
• Monitor for portal hypertension (thrombocytopenia, splenomegaly, varices); upper GI endoscopy if signs of portal hypertension
• CF-related cirrhosis with portal hypertension is an indication for combined lung–liver transplant evaluation

Nutritional Management

A high-calorie, high-fat diet (35–45% of energy from fat for PI patients) with adequate protein is essential. CF dietitians are integral to the multidisciplinary team.

• Caloric targets: 110–200% of estimated average requirement (EAR) for age; individualised by a CF dietitian
• Oral nutritional supplements (e.g., Sustagen®, Ensure Plus®) for those failing to meet targets
• Enteral feeding (nasogastric or gastrostomy) for patients with BMI <25th percentile or failing to thrive despite oral supplementation — common in adolescents and adults with advanced disease
• CFTR modulator therapy often improves appetite and weight; monitor and adjust caloric targets accordingly

Bone Disease

Low bone mineral density (BMD) is common in CF due to chronic inflammation, malabsorption of vitamin D and calcium, delayed puberty, corticosteroid use, and hypogonadism. DEXA scan should be performed from age 8–10 years and repeated every 2–5 years. Calcium (1,000–1,500 mg/day) and vitamin D supplementation (target 25-OH-vitamin D >75 nmol/L) are standard. Bisphosphonates may be considered for adults with T-score ≤ −2.5 or fragility fracture, under specialist guidance.

Lung Transplant Evaluation

Indications for transplant referral:

• FEV₁ <30% predicted (or <50% with rapid decline >20% in 12 months)
• Increasing frequency/severity of pulmonary exacerbations requiring IV antibiotics
• Recurrent massive haemoptysis not amenable to embolisation
• Refractory pneumothorax
• Respiratory failure (hypoxia, hypercapnia)
• CFRD with declining FEV₁
• Deteriorating nutritional status despite maximal support

Contraindications / relative contraindications: Active B. cenocepacia (genomovar III) infection (many Australian centres), active NTM with uncontrolled infection, active malignancy, non-compliance, active substance abuse, severe psychosocial issues. Chronic P. aeruginosa is NOT a contraindication.

1. 1. Cystic Fibrosis Australia. Australian Cystic Fibrosis Data Registry Annual Report 2022. North Ryde, NSW: Cystic Fibrosis Australia; 2023.
2. 2. Castellani C, Duff AJA, Bell SC, et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018;17(2):153–178.
3. 3. Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381(19):1809–1819.
4. 4. Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial (VX-445-104). Lancet. 2019;394(10212):1940–1948.
5. 5. Australian Government Department of Health and Aged Care. Pharmaceutical Benefits Scheme — Elexacaftor with tezacaftor with ivacaftor (Trikafta). Canberra: Commonwealth of Australia; 2022. Available at: pbs.gov.au.
6. 6. Döring G, Flume P, Heijerman H, Elborn JS, et al. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J Cyst Fibros. 2012;11(6):461–479.
7. 7. Taccetti G, Bianchini E, et al. Pseudomonas aeruginosa eradication in cystic fibrosis: a consensus statement from the Italian Society of Cystic Fibrosis. J Cyst Fibros. 2020;19(2):195–203.
8. 8. Moran A, Brunzell C, Cohen RC, et al. Clinical care guidelines for cystic fibrosis–related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33(12):2697–2708.
9. 9. Haworth CS, Bilton D, Elborn JS. Long-term safety and efficacy of inhaled dry powder mannitol in the treatment of cystic fibrosis. J Cyst Fibros. 2014;13(4):418–425.
10. 10. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367–416.
11. 11. Snijders D, Bengt K, et al. Antibiotic therapies for Staphylococcus aureus lung infections in cystic fibrosis. Cochrane Database Syst Rev. 2017;4:CD006851.
12. 12. Australian Institute of Health and Welfare (AIHW). Aboriginal and Torres Strait Islander Health Performance Framework 2023. Canberra: AIHW; 2023.
13. 13. NHMRC Centre of Research Excellence in Cystic Fibrosis. Australian CF Clinical Practice Guidelines. Melbourne: Murdoch Children's Research Institute; 2020 (updated 2023).
14. 14. Sly PD, Gangell CL, Chen L, et al. Risk of bronchiectasis in cystic fibrosis detected by computed tomography. N Engl J Med. 2013;369(23):2212–2221.
15. 15. Dijk FN, McKay K, Barzi F, et al. Improved survival in cystic fibrosis in Australia: the impact of newborn screening and CFTR modulator therapy. J Cyst Fibros. 2022;21(5):767–774.