Volume 218 - Issue 3
Overcoming the burden of cystic fibrosis
Author: John Massie
Med J Aust 2023; 218 (3): 118-119. || doi: 10.5694/mja2.51837
Published online: 20 February 2023
Published online: 20 February 2023
Effective modulator treatments now available for most people will probably add years to their lives
Effective modulator treatments now available for most people will probably add years to their lives
The report by Lin and colleagues in this issue of the Journal on cystic fibrosis diagnosed during adulthood1 is a timely reminder of the importance of the disorder. More than 4000 people in Australia have cystic fibrosis,2 and one in 25 carry disease‐relevant gene mutations.3 Further, despite routine screening of newborns, clinical diagnosis remains important, and late diagnosis is associated with lower life expectancy.4 Finally, new therapies that target its genetic bases substantially improve outcomes for patients.5
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Of the more than 2000 identified mutations, the most frequent mutant allele is p.F508del (about 70% of all mutants); ten further mutants account for most of the remaining 30%.3 CFTR is an epithelial transport protein in the bronchi, pancreatic exocrine ducts, biliary ducts, gastrointestinal mucosa, eccrine sweat ducts, and vas deferens.6 The typical clinical manifestations (experienced by 85% of people with cystic fibrosis) consequently include suppurative lung disease, pancreatic exocrine insufficiency, and elevated sweat electrolyte levels.6 However, pancreatic exocrine function is partially retained in about 15% of people with cystic fibrosis, as certain CFTR mutations allow residual CFTR electrolyte transport.7 Isolated organ involvement, such as sinusitis, recurrent pancreatitis, or congenital bilateral absence of the vas deferens, are generally regarded as CFTR‐related diseases rather than cystic fibrosis per se.7,8
Lin and colleagues analysed data from the Australian Cystic Fibrosis Data Registry, which captures data for more than 90% of people in Australia with cystic fibrosis, highlighting the importance of such databases for understanding disease epidemiology.2 The disorder is usually diagnosed in infants after newborn screening, but the authors report that 20% of people were more than 50 years old when diagnosed.1 Adults may be diagnosed with cystic fibrosis because they were missed by newborn screening (about 5% of people with cystic fibrosis), were born before newborn screening commenced (in 1981 in New South Wales, 2001 in Western Australia), or were born in countries where newborn screening for cystic fibrosis is not undertaken.9
Lin and her co‐authors found that 70% of people with cystic fibrosis had at least one p.F508del mutation. The mode of presentation was predominantly pulmonary with suppurative bronchitis, male infertility (the Fallopian tubes, with a different embryological origin, are unaffected by the disease), and gastrointestinal symptoms, including constipation or distal intestinal obstruction syndrome (caused by more viscous intestinal secretions), rectal prolapse, and pancreatitis. Interestingly, 32% of people had pancreatic insufficiency, suggesting they had classic cystic fibrosis and minimal CFTR function. Sweat chloride values, the basis of diagnostic testing for cystic fibrosis, were not reported.1
Among the important lessons of the registry study by Lin and colleagues is that people of any age with clinical symptoms suggesting cystic fibrosis should undergo sweat chloride tests.8,10 Sweat testing is preferred to gene testing in the first instance because most CFTR gene tests are panel tests limited to 12–170 mutations, and may miss some cases,11 while CFTR exome sequencing may detect mutations of uncertain clinical significance.12 Both tests are now subsidised under the Medical Benefits Schedule (item 73345), but only once per person. It is therefore better to undertake CFTR mutation analysis after the clinical phenotype has been assessed by a physician familiar with cystic fibrosis and sweat chloride testing.
In 2022, the highly effective CFTR modulator and chloride channel opener combination preparation elexacaftor–tezacaftor–ivacaftor (Trikafta) was added to the Pharmaceutical Benefits Scheme for people with cystic fibrosis with one or two p.F508del mutations.13 Trikafta restores CFTR function in vitro, and in a phase III randomised controlled trial improved lung function by 10%, increased weight by 3kg, and reduced sweat chloride levels to within the normal range.5 The benefits of Trikafta have been life‐changing for many patients, but it is too early to determine whether they are sustained long term or the agent can be considered a cure.14 Trikafta is approved for use from six years of age, but the limit will probably soon be reduced to two years, and will perhaps ultimately be permitted from the time of diagnosis after newborn screening.
Similar modulators are available for people with other CFTR mutations, but 10–15% have disease not amenable to current therapies. Nevertheless, effective treatments are at last available for most people and will probably add years to their lives. As life expectancy for people with late diagnoses in the analysis by Lin and colleagues was still lower than for other Australians, and most had at least one p.F508del CFTR mutation, it is likely they would benefit from modulator therapy. What this means for the adult patients with cystic fibrosis “lost” among other patients in bronchitis clinics is uncertain, but I suspect that many more sweat chloride tests will be needed. Modulatory therapy may also benefit people with clinically significant but non‐pulmonary manifestations of cystic fibrosis.
Relatives of people with cystic fibrosis (diagnosed at any age) may also be at risk of the disorder or at least carry relevant mutations (including 50% of their siblings).3 Cascade family testing can identify carriers and offer them genetic counselling; in Victoria, this has resulted in a 10% reduction in the live birth prevalence of cystic fibrosis since the start of newborn screening in 1989.15 However, most people with cystic fibrosis do not have family histories of the disease, and only population‐based carrier screening programs assist couples avoid having children with cystic fibrosis.16 Such programs are available in Australia, but only on a fee‐for‐service basis.17 How people might choose to use this information in the era of highly effective modulator therapy remains to be seen.
Competing interests
No relevant disclosures.
References
- Lin A, Wong K, Visser SK, et al. Diagnosis of cystic fibrosis in adults: Australian Cystic Fibrosis Data Registry data, 2000–2019. Med J Aust 2023; 218: 138‐139.
- Ruseckaite R, Salimi F, Earnest A, et al. Survival of people with cystic fibrosis in Australia. Sci Rep 2022; 12: 19748.
- Bobadilla JL, Macek M, Fine JP, Farrell PM. Cystic fibrosis: a worldwide analysis of CFTR mutations. Correlation with incidence data and application to screening. Hum Mutat 2002; 19: 575‐606.
- Jain R. Diagnosing cystic fibrosis in adults: better late than never. Ann Am Thorac Soc 2018; 15: 1140‐1141.
- Keating D, Marigowda G, Burr L, et al. VX‐445–tezacaftor–ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018; 379: 1612‐1620.
- Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med 2005; 352: 1992‐2001.
- Chillón M, Casals T, Mercier B, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 1995; 332: 1475‐1480.
- Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr 2017; 181 (Suppl): S4‐S15.
- Massie J, Clements B; Australian Paediatric Respiratory Group. Diagnosis of cystic fibrosis after newborn screening: the Australasian experience: twenty years and five million babies later: a consensus statement from the Australasian Paediatric Respiratory Group. Pediat Pulmonol 2005; 39: 440‐446.
- Massie RJ, Curnow L, Glazner J, et al. Lessons learned from 20 years of newborn screening for cystic fibrosis. Med J Aust 2012; 196: 67‐70. https://www.mja.com.au/journal/2012/196/1/lessons‐learned‐20‐years‐newborn‐screening‐cystic‐fibrosis
- Mishra A, Greaves R, Massie J. The relevance of sweat testing for the diagnosis of cystic fibrosis in the genomic era. Clin Biochem Rev 2005; 26: 135‐153.
- Sosnay PR, Salinas DB, White TB, et al. Applying cystic fibrosis transmembrane conductance regulator genetics and CFTR2 data to facilitate diagnoses. J Pediatr 2017; 181 (Suppl): S27‐S32.
- Department of Health and Aged Care. Landmark PBS listing for Australians with cystic fibrosis [media release]. 27 Mar 2022. https://www.health.gov.au/ministers/the‐hon‐greg‐hunt‐mp/media/landmark‐pbs‐listing‐for‐australians‐with‐cystic‐fibrosis (viewed Jan 2023).
- Burgel PR, Durieu I, Chiron R, et al; French Cystic Fibrosis Reference Network Study Group. Rapid improvement after starting elexacaftor–tezacaftor–ivacaftor in patients with cystic fibrosis and advanced pulmonary disease. Am J Respir Crit Care Med 2021; 204: 64‐73.
- Massie J, Curnow L, Gaffney L, et al. Declining prevalence of cystic fibrosis since the introduction of newborn screening. Arch Dis Child 2010; 95: 531‐533.
- Massie J, Ioannou L, Delatycki M, et al. Prenatal and preconception population carrier screening for cystic fibrosis in Australia: where are we up to? Cystic fibrosis carrier screening. Aust N Z J Obstet Gynaecol 2014; 54: 503‐509.
- Archibald AD, Smith MJ, Burgess T, et al. Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests. Genet Med 2018; 20: 513‐523.
Provenance: Commissioned; not externally peer reviewed.