Cystic fibrosis

• Cystic fibrosis is an autosomal recessive disease caused by variants in the CFTR gene, which encodes a phosphorylation-activated chloride and bicarbonate channel in epithelial cells.
• Loss of channel function dehydrates airway surface liquid and thickens mucus, setting up a cycle of infection, inflammation and bronchiectasis, while obstructed pancreatic ducts destroy enzyme-producing tissue and cause malabsorption.
• It is the most common life-threatening autosomal recessive disease in people of European descent, but incidence ranges from about 1 in 1,350 births in Ireland to about 1 in 25,000 in Finland. ^[1]
• Diagnosis rests on sweat chloride testing and CFTR genotyping; newborn screening measures immunoreactive trypsin (IRT) in dried blood, usually followed by mutation analysis.
• Modern care mixes airway clearance, inhaled and systemic antibiotics, high-calorie nutrition with pancreatic enzyme replacement, glucose management and CFTR modulators that improve or restore channel function for eligible genotypes.

By the end of this page you should be able to:

1. Explain how loss of CFTR function turns a thin layer of airway liquid into chronic mucus plugging and bronchiectasis.
2. Name the six mutation classes and say which predict severe, pancreatic-insufficient disease.
3. Interpret sweat chloride concentrations and describe how newborn screening leads to diagnosis.
4. Plan chronic pulmonary care: airway clearance, mucoactive therapy, antibiotic prophylaxis and treatment, and infection prevention.
5. Manage pancreatic insufficiency, cystic fibrosis-related diabetes, liver disease and male infertility.
6. Explain how CFTR modulators work, who can receive them and what clinical benefits are expected.

The disease was described in 1938, when most affected children died in the first year; CFTR was identified in 1989. ^[1] Before that discovery the basic defect was already recognised as excess salt in sweat: a child with cystic fibrosis who is kissed on the forehead tastes salty, because chloride is not reabsorbed from sweat. ^[5]

CFTR sits on the long arm of chromosome 7 (7q31.2). It contains 27 coding exons spread over about 190 kb of genomic DNA and is transcribed into a 6.2 kb messenger RNA. ^[5] The protein has 1,480 amino acids and belongs to the ATP-binding cassette transporter family (ABCC7). It is the only member of that family with a regulatory domain and the only one that works as an ion channel rather than a transporter. ^[5]

The channel is made of five domains: two transmembrane domains (each with six membrane-spanning segments that form the pore), two nucleotide-binding domains and a regulatory domain. ^[5] In the apical membrane of epithelial cells it acts as a cyclic-AMP-dependent, phosphorylation-activated channel for chloride and bicarbonate, and it also modulates the epithelial sodium channel (ENaC). ^[5] Protein kinase A and protein kinase C phosphorylate serine and threonine residues on the regulatory domain, and binding and hydrolysis of ATP at the nucleotide-binding domains open and close the pore. ^[5]

More than 2,000 CFTR variants have been reported, and about 432 are annotated in the clinical and functional translation database CFTR2, of which 352 are accepted as disease-causing. ^[5] Mutations are grouped by the molecular defect they produce:

The most common disease-causing variant is F508del, a deletion of phenylalanine at position 508. It is a class II mutation: the protein misfolds in the endoplasmic reticulum, is arrested by quality control and degraded before it reaches the cell surface. ^[3][5] F508del accounts for about 70% of cystic fibrosis alleles worldwide and is carried by roughly 82% of people with cystic fibrosis in at least one allele. ^[3][5] Only about six mutations have a prevalence of 1% or more, and about 50 have a prevalence of 0.1% or more, so most people with unusual genotypes carry rare variants. ^[5]

Mutations in classes I, II and III are usually associated with classical, severe cystic fibrosis; those in classes IV, V and VI are usually associated with milder or atypical disease, with pancreatic sufficiency and later bacterial colonisation. ^[1][5] People carrying at least one mild mutation have an estimated median survival about ten years longer than those with severe genotypes. ^[1] CFTR genotype does not explain everything: lung severity is also modified by other genes, by the environment and by adherence to treatment. ^[5]

Some CFTR variants do not cause full cystic fibrosis but produce CFTR-related disorders, such as congenital bilateral absence of the vas deferens, recurrent or chronic pancreatitis and disseminated bronchiectasis. ^[1] These patients usually have less severe symptoms and do not meet diagnostic criteria for cystic fibrosis; they still need appropriate counselling and, sometimes, CFTR modulator therapy.

Inheritance is autosomal recessive: a child is affected only if both CFTR alleles carry a disease-causing variant, receiving one from each parent. A carrier has one normal and one faulty allele and is healthy. ^[1]

Carrier frequency varies with ethnicity. In people of European descent cystic fibrosis has traditionally been quoted at about 1 in 2,500 live births. ^[1] Newborn screening data suggest the real incidence is lower and is now estimated at 1 in 3,000 to 1 in 6,000 births in such populations, corresponding to carrier rates of about 1 in 28 to 1 in 40. ^[1] Incidence by region varies widely: about 1 in 1,353 in Ireland, about 1 in 4,500 in Western Europe, about 1 in 6,000 in Northern and Central Europe, about 1 in 3,000 in Australasia, about 1 in 3,300 in Canada, about 1 in 4,000 in the United States, and about 1 in 25,000 in Finland. ^[1] Latin and South America average about 1 in 8,000 to 1 in 10,000; incidence in Asia ranges from about 1 in 2,560 in Jordan to about 1 in 350,000 in Japan; and in Africa data remain sparse. ^[1] Founder effects can raise incidence in isolates, for example about 1 in 569 in the Amish of Ohio and about 1 in 902 in Saguenay-Lac-Saint-Jean in Quebec. ^[1]

Because the carrier rate is high in some populations, many countries offer preconception or antenatal carrier screening. Population screening panels concentrate on mutations that cause classical cystic fibrosis; rare or mild variants are less useful for population screening because their clinical meaning is harder to predict.

Newborn screening combines a blood spot immunoreactive trypsin (IRT) test with CFTR gene analysis. ^[1][2] IRT is a pancreatic enzyme precursor that is high when pancreatic ducts are obstructed. Coupling IRT with mutation searching removes the need for a second blood sample, reduces family anxiety, and leads to earlier diagnosis and treatment. ^[1] Screening finds many more cases early; it is associated with better nutritional status, lower infection rates, better lung function and fewer hospital admissions. ^[1] A positive screen is confirmed with a sweat chloride test and, usually, CFTR genotyping at a specialist centre. ^[2]

Cystic fibrosis affects more than 90,000 people worldwide, unevenly distributed: about half of registered patients live in North America and Europe has the next largest group. ^[5] Its incidence has declined in many regions for several reasons: larger population admixture, falling consanguinity, lower fertility rates, antenatal diagnosis and family and population carrier screening. ^[1] In Massachusetts, USA, incidence fell after US population carrier screening was recommended in 2003; in Israel it fell by roughly 60% over 22 years after population screening began in 1999. ^[1]

Survival has improved dramatically. When the disease was first described in 1938 most children died in the first year; in the 1960s few survived beyond age five. Today the median age of survival is close to 50 years in several countries (about 47 years in the United Kingdom and the United States, about 44 in Ireland, about 52 in Canada), and adults make up more than half of patients (over 60% in Canada). ^[1] Patients carrying at least one mild mutation live about ten years longer. ^[1]

There is no modifiable risk factor for the person who inherits two disease-causing variants. Risk increases with:

• a family history of cystic fibrosis or of CFTR-related disorders;
• parental consanguinity, which is why incidence is higher in regions where cousin marriage is common;
• belonging to a population with a high carrier rate, such as people of Northern European descent, and to some regional founder populations.

Genetic counselling for carrier couples is essential; specialist services provide individual risk figures.

Everything in cystic fibrosis follows from loss of CFTR anion transport.

1. Airway surface liquid dehydrates. Loss of chloride and bicarbonate transport, together with excessive sodium absorption through ENaC, dries the thin liquid layer that normally floats on airway mucosa. ^[5]
2. Mucus becomes thick and sticky. Mucins are not flushed and hydrated, so they form dense plugs. ^[5]
3. Mucociliary clearance fails. Cilia cannot move plugs, so bacteria are not cleared.
4. Infection and inflammation become chronic. Early isolates are often Staphylococcus aureus or Haemophilus influenzae; later, Pseudomonas aeruginosa dominates and becomes mucoid. ^[2] Repeated neutrophilic inflammation damages airways and produces bronchiectasis.
5. Progressive lung disease. Bronchiectasis, air trapping and, in advanced cases, respiratory failure develop over years.
6. Extrapulmonary consequences. Pancreatic ducts obstruct and enzymes autodigest the gland; bile canaliculi damage the liver; sweat chloride is high because chloride is not reabsorbed; and the vas deferens fails to develop in almost all males.

CFTR also transports bicarbonate, which matters: bicarbonate is needed for proper mucin unfolding and for killing bacteria on airway surfaces. ^[5]

Macroscopic findings include mucoid impaction of airways, atelectasis, chronic inflammation and, in advanced disease, bronchiectasis and cysts. Microscopically there is goblet-cell hyperplasia, squamous metaplasia, and dense neutrophilic infiltrates in bronchial walls. ^[1] In the pancreas ducts are dilated and plugged with eosinophilic material, acini are destroyed, and the gland is largely replaced by fat and fibrous tissue (which is why it was originally called cystic fibrosis of the pancreas). ^[1] Liver pathology ranges from focal biliary cirrhosis to multilobular cirrhosis; meconium ileus produces inspissated, rubbery meconium in the distal ileum. ^[2]

People with cystic fibrosis describe a "lifelong cough" that is usually productive, especially in the morning; repeated chest infections; wheezing; breathlessness on exertion; and frequent sinus congestion. ^[2] In babies the first clue may be meconium ileus: failure to pass meconium within 24 to 48 hours, abdominal distension and vomiting. ^[2] Later, parents may report failure to thrive despite a good appetite, large foul-smelling greasy stools (steatorrhoea), constipation, rectal prolapse, or nasal polyps. ^[2] Adults may present with infertility, recurrent sinus disease or pancreatitis. ^[2]

Some people are diagnosed in adulthood after years of being treated for "asthma" or "bronchiectasis", because their mutation produced only partial CFTR dysfunction and symptoms were mild. ^[1]

• General: failure to thrive or underweight, clubbing of fingers, signs of vitamin deficiency. ^[2]
• Chest: hyperinflation, crackles and wheezes; coarse breath sounds in children. ^[2]
• Nose: nasal polyps or chronic pansinusitis (prevalence increases with age). ^[2]
• Abdomen: distension, hepatosplenomegaly in those with liver disease, palpable faecal masses.
• Reproductive: obstructive azoospermia in almost all males. ^[2]

Measure weight and height (or length in infants) at every visit, because poor growth is an early and sensitive indicator of disease control. ^[2]

The main alternatives depend on which system is affected first:

NICE recommends assessment for cystic fibrosis and sweat or gene testing in people with a family history, meconium ileus, failure to thrive, recurrent lung disease, chronic sinus disease, malabsorption, rectal prolapse in children, pancreatitis, obstructive azoospermia, or pseudo-Bartter syndrome. ^[2]

Sweat testing uses quantitative pilocarpine iontophoresis. Cystic Fibrosis Foundation consensus guidance (reflected in the 2017 review below) classifies sweat chloride as follows for people older than 6 months:

Gene testing identifies the variants a person carries. The diagnosis is supported when two disease-causing CFTR variants are present on different alleles together with a compatible phenotype or positive screening result. ^[2][3] Gene testing also determines eligibility for CFTR modulators and allows cascade testing of relatives.

• Respiratory samples. Sputum when possible, otherwise cough swabs or nasopharyngeal aspirate, are cultured at each review to detect Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, Haemophilus influenzae, non-tuberculous mycobacteria and Aspergillus fumigatus complex. ^[2]
• Lung function. Spirometry (FEV1, FVC, FEF25-75) in those able to perform it; measurement of lung clearance index or chest imaging when spirometry is normal but symptoms exist. ^[2]
• Chest imaging. A chest X-ray, and in children a low-dose CT scan when one has not been performed, to look for early bronchiectasis. ^[2]
• Pancreas and nutrition. Stool elastase to test for exocrine pancreatic insufficiency; energy intake and vitamin levels at annual review. ^[2]
• Liver. Clinical assessment and liver function tests annually, with ultrasound if tests are abnormal. ^[2]
• Glucose. Testing for cystic fibrosis-related diabetes from age 10 years. ^[2]
• Bone. Bone mineral density assessment in those with risk factors such as frequent corticosteroid use, frequent intravenous antibiotics, severe lung disease, undernutrition, previous low-trauma fractures, or transplantation. ^[2]

Diagnosis is made in one of three ways: ^[2]

1. Positive screening in an asymptomatic person (blood spot IRT plus sweat and gene tests for confirmation);
2. Clinical manifestations supported by sweat chloride or CFTR gene test results;
3. Clinical manifestations alone, in the rare person with symptoms but normal sweat or gene tests.

A positive or equivocal sweat result, a clinical picture suggesting cystic fibrosis despite normal tests, or any gene test showing one or more CFTR mutations warrants referral to a specialist CF centre. ^[2]

People with intermediate sweat chloride plus mutations of uncertain consequence may be labelled CFTR-related metabolic syndrome (CRMS, sometimes CFSPID). They are usually healthy but need follow-up, because a proportion may later develop cystic fibrosis. ^[3]

Care is best delivered by a specialist multidisciplinary CF team, ideally at a CF centre, with shared care when appropriate. ^[2] Teams include specialist physicians, nurses, physiotherapists, dietitians, pharmacists, clinical psychologists, and access to microbiology, diabetes, gastroenterology, hepatology, surgery and palliative care expertise. ^[2] Care plans are made at least annually, but more frequently in infancy: weekly in the first month, every 4 weeks from 1 to 12 months, every 6 to 8 weeks from 1 to 5 years, every 8 to 12 weeks over 5 years, and every 3 to 6 months for adults. ^[2]

• Discuss and teach airway clearance techniques to everyone, whether or not they have clinical lung disease; offer training to those with lung disease. ^[2]
• Assess each person's ability to clear mucus individually; choose a technique that suits them and that they will actually use; reassess and change if it is not working. ^[2]
• High-frequency chest wall oscillation is not offered routinely because it is less effective than other methods; specialist teams reserve it for exceptional circumstances. ^[2]
• Consider non-invasive ventilation when standard clearance fails in moderate to severe lung disease. ^[2]
• Regular exercise improves both lung function and overall fitness; individualised exercise programmes should be offered and reviewed. ^[2]

• Offer a mucoactive agent when there is clinical evidence of lung disease. ^[2]
• RhDNase (dornase alfa) is the first-choice mucoactive agent. ^[2]
• If response to rhDNase is inadequate, consider rhDNase plus hypertonic sodium chloride, or hypertonic sodium chloride alone. ^[2]
• Consider mannitol dry powder for inhalation for children and young people who cannot use rhDNase and hypertonic saline because of ineligibility, intolerance or inadequate response. ^[2]
• In adults who cannot use rhDNase, mannitol dry powder is recommended as an option under technology appraisal guidance. ^[2]

Staphylococcus aureus

• Offer flucloxacillin prophylaxis against respiratory Staphylococcus aureus from diagnosis up to age 3 years, and consider continuing to age 6 years. ^[2]
• If a child on prophylaxis cultures Staphylococcus aureus, review adherence, start treatment-dose anti-staphylococcal antibiotics, then restart prophylaxis. ^[2]
• If a person not on prophylaxis develops a new Staphylococcus aureus infection, use an oral anti-staphylococcal agent if they are well, or broad-spectrum intravenous or oral antibiotics if unwell. ^[2]
• Consider a long-term suppressive antibiotic for chronic methicillin-sensitive Staphylococcus aureus (MSSA) when pulmonary status is stable. ^[2]
• Do not routinely suppress chronic methicillin-resistant Staphylococcus aureus (MRSA) in stable disease; seek specialist microbiological advice for new MRSA, or if a patient with chronic MRSA becomes unwell. ^[2]

Pseudomonas aeruginosa

• New infection: start eradication therapy with oral or intravenous antibiotics together with an inhaled antibiotic if the person is well; with intravenous antibiotics plus an inhaled antibiotic if unwell; then a further extended course of oral and inhaled antibiotics. ^[2]
• If eradication fails, offer sustained inhaled antibiotic therapy; nebulised colistimethate sodium is first line. ^[2]
• Chronic infection causing an exacerbation: treat with an oral antibiotic or two intravenous antibiotics of different classes depending on severity. ^[2]
• Repeated exacerbations despite treatment should prompt a change of regimen. ^[2]
• If the patient deteriorates despite regular inhaled colistimethate, consider nebulised aztreonam, nebulised tobramycin, or tobramycin dry powder inhalation. ^[2]

Burkholderia cepacia complex

• New infection: combination intravenous antibiotics with specialist microbiological advice. ^[2]
• There is no evidence to support routine antibiotic suppression of chronic Burkholderia cepacia complex in stable patients; discuss risks such as drug toxicity. ^[2]
• Exacerbations: combination oral or intravenous antibiotics with microbiology advice. ^[2]
• Declining status: consider a sustained inhaled antibiotic; stop if no benefit. ^[2]

Other organisms

• Haemophilus influenzae: treat with an appropriate oral or intravenous antibiotic according to severity. ^[2]
• Non-tuberculous mycobacteria: repeat any positive result; if persistently positive, CT chest; consider eradication therapy when the patient is clinically unwell or CT shows compatible changes. ^[2]
• Aspergillus fumigatus complex: do not routinely suppress chronic infection in stable disease. In patients with declining status consider an antifungal, with microbiology advice, and stop or change if there is no benefit. ^[2]
• For elevated aspergillus serology with declining lung function despite optimised treatment, consider treatment for allergic bronchopulmonary aspergillosis or aspergillus airway disease. ^[2]
• Exacerbations without an identified cause: broad-spectrum oral or intravenous antibiotics, continuing to collect samples. ^[2]

Immunomodulatory therapy

Long-term azithromycin at an immunomodulatory dose is offered to people with deteriorating lung function or repeated exacerbations. ^[2] If deterioration continues despite azithromycin, stop it and consider oral corticosteroids. ^[2] Inhaled corticosteroids are not recommended as immunomodulatory treatment for cystic fibrosis. ^[2]

People with cystic fibrosis can transmit serious organisms to each other. Clinics separate patients by microbiological status, clean spirometry and nebulising equipment thoroughly, and avoid shared facilities such as hydrotherapy pools between infected and non-infected patients. ^[2] Patients should be told how to contact other CF patients safely, for example through online support groups without meeting in person. ^[2]

CFTR modulators are drugs that correct, potentiate, stabilise or amplify CFTR protein function. They are genotype-specific: the mutation class and the individual variant determine which drug (if any) might help. ^[5] The five mechanistic groups are potentiators, correctors, stabilisers, read-through agents and amplifiers. ^[5]

• Potentiators such as ivacaftor increase channel open probability at the membrane and entered practice in 2012 for patients aged at least 6 years carrying at least one G551D mutation, a class III gating variant. ^[5]
• Correctors such as lumacaftor and tezacaftor address the folding and trafficking defect of F508del; combined with a potentiator they improve outcomes in F508del homozygous and some heterozygous patients. ^[5]
• Triple combination therapy with elexacaftor, tezacaftor and ivacaftor improves lung function by up to 14 percentage points of predicted FEV1, lowers sweat chloride, reduces exacerbations and improves quality of life in patients with at least one F508del allele. ^[5] Long-term use of ivacaftor alone has also been associated with a reduced need for lung transplantation. ^[5]

In the United Kingdom (NICE technology appraisals linked from the CF guideline) the following options are currently recommended for eligible genotypes:

• elexacaftor-tezacaftor-ivacaftor (plus ivacaftor) for some people aged 2 years and over; ^[2]
• tezacaftor-ivacaftor (plus ivacaftor) for some people aged 6 years and over; ^[2]
• lumacaftor-ivacaftor for some people aged 1 year and over; ^[2]
• vanzacaftor-tezacaftor-deutivacaftor for some people aged 6 years and over. ^[2]

Eligibility depends on genotype, age, renal and hepatic function, and local availability. Use the product label or local formulary for dosing, monitoring and interactions; many of these agents require liver function testing. ^[2]

Clinical benefits reported with ivacaftor include sweat chloride approaching normal levels, better BMI, exercise capacity and wellbeing, and changes in pathogen detection. ^[5] Modulators are not a cure: lung function still declines, only more slowly, and exacerbations still occur. ^[5]

Pancreatic exocrine insufficiency is common; severity depends on mutation class, with milder genotypes more likely to be pancreatic sufficient.

• Testing and treating. Test for exocrine pancreatic insufficiency with a non-invasive technique such as stool elastase. ^[2] Offer oral pancreatic enzyme replacement therapy, adjusting the dose as needed to minimise symptoms and signs of malabsorption. ^[2] If malabsorption persists despite optimal enzyme replacement, consider an acid suppressant such as an H2 receptor antagonist or proton pump inhibitor. ^[2]
• Diet. A specialist dietitian advises on high calorie intake, usually 1.2 to 1.5 times the daily recommended intake for age. ^[4] Increase portion size and high-energy foods first; if that fails try oral nutritional supplements, then enteral tube feeding; for adults a short trial of an appetite stimulant may help. ^[2]
• Fat-soluble vitamins. Routine supplementation with cystic fibrosis-specific multivitamins, including vitamins A, D, E and K, because malabsorption causes deficiency. ^[1][4]
• CF-related diabetes diet. People with CFRD still need a high-calorie CF diet: calories 1.2 to 1.5 times the daily recommended intake, fat unrestricted at 35 to 40% of calories, protein about 1.5 to 2.0 times the daily recommended intake, liberal salt, and no calorie or carbohydrate restriction. ^[4]

CFRD is the most common comorbidity in CF, occurring in about 20% of adolescents and 40 to 50% of adults. ^[4] It is caused mainly by insulin insufficiency with fluctuating insulin resistance during illness, and it harms lung function and survival more in women. ^[4]

• Screening. Annual screening starts by age 10 years in all people without CFRD, using a 2-hour 75 g oral glucose tolerance test. ^[2][4] A1C is not sensitive enough to screen. ^[4] Screening is also needed during acute illness, continuous enteral feeding, pregnancy and before transplantation. ^[4]
• Diagnosis. During stable health, standard ADA diabetes criteria apply (2-hour OGTT plasma glucose at least 200 mg/dL or 11.1 mmol/L, fasting plasma glucose at least 126 mg/dL or 7.0 mmol/L, A1C at least 6.5% with the caution that A1C is often spuriously low in CF, or classical symptoms with random glucose at least 200 mg/dL or 11.1 mmol/L). ^[4] A diagnosis can also be made when hyperglycaemia persists for more than 48 hours during acute illness. ^[4]
• Treatment. CFRD is treated with insulin; oral hypoglycaemic agents are not as effective and are not recommended outside clinical research. ^[4] Basal-bolus or pre-meal insulin is used and requirements rise two- to fourfold during illness, then fall back over 4 to 6 weeks. ^[4] Patients on insulin check blood glucose at least 3 times daily, aim for an A1C around 7% (individualised), and have A1C measured every 3 months. ^[4] Moderate aerobic exercise of at least 150 minutes per week is advised. ^[4]

Chronic liver disease becomes more common with age until early adulthood. ^[2] At annual review perform a clinical assessment and liver function tests. ^[2] If tests are abnormal, do a liver ultrasound and consider ursodeoxycholic acid. ^[2] Refer to a liver specialist for persistently abnormal tests despite treatment, chronic progressive disease, liver failure, portal hypertension, haematemesis, splenomegaly or abnormal ultrasound. ^[2]

• Bone health: offer DXA scanning when risk factors are present and seek specialist advice if the Z or T score is under -2.0 or -2.5 respectively. ^[2]
• Psychological and social support: specialist clinical psychologists assess mental health, quality of life and adherence at annual review; refer severe conditions. ^[2]
• Transition: begin discussing transition to adult services at age 12 years, with coordinated pathways. ^[2]
• End of life: palliative care access when appropriate. ^[2]

NICE lists common complications of cystic fibrosis. ^[2] A few important frequencies and warnings:

• Meconium ileus affects about 1 in 7 newborn babies, causing intestinal obstruction in the first days of life. ^[2]
• Fat-soluble vitamin deficiency (A, D, E and K) is common in pancreatic-insufficient disease. ^[2]
• Distal intestinal obstruction syndrome (DIOS) mimics acute abdomen; first-line treatment is oral or enteral diatrizoate (Gastrografin), second line macrogol solutions, with surgery as a last resort. ^[2]
• Nasal polyps and sinusitis increase in prevalence with age. ^[2]
• Chronic liver disease increases in prevalence until early adulthood. ^[2]
• Male infertility is caused by obstructive azoospermia in almost all males with CF; female fertility is reduced but pregnancy is possible. ^[2]
• Cystic fibrosis-related diabetes is uncommon under 10 years but rises with age, affecting up to 1 in 2 adults. ^[2]
• Reduced bone mineral density and osteoporosis are common. ^[2]
• Urinary stress incontinence, arthralgia and muscle pains are frequent. ^[2]
• Renal calculi affect about 1 in 20 adults. ^[2]
• Less common problems include CF-related arthritis and delayed puberty in severe disease. ^[2]

For advanced, life-limiting lung disease, lung transplantation is the only remaining option that can improve survival and quality of life; eligibility and timing are decided by the multidisciplinary and transplant teams.

Prognosis has been transformed by multidisciplinary care, better nutrition, inhaled therapies, early diagnosis through newborn screening and transplantation. ^[1] Median age of survival is now close to 50 years, though it remains much lower in some regions. ^[1][5] Prognosis is worse with low FEV1 (under 30% of predicted) ^[1], female sex, later diagnosis, severe CFTR genotype, pancreatic insufficiency, early Pseudomonas colonisation, lower nutritional status, diabetes and lower socioeconomic status. ^[1] As patients survive longer, new problems such as CFRD, metabolic bone and kidney disease, and some cancers become more common. ^[5]

• Infants and children: watch for meconium ileus, failure to thrive and rectal prolapse; start Staphylococcus aureus prophylaxis; maintain growth; encourage exercise.
• Adolescents: begin transition discussions at age 12 years; adherence, education, career, fertility and body image all matter. ^[2]
• Pregnancy: CFRD screening at both 12 to 16 and 24 to 28 weeks if not known to have CFRD; manage with respiratory, obstetric and diabetes teams. ^[4]
• Adults: fertility counselling; men with obstructive azoospermia may need sperm retrieval and assisted reproduction.

• When quantitative sweat testing is unavailable, diagnose on strong clinical grounds plus family history while referring for confirmation. ^[2]
• Basic airway clearance (positioning, breathing exercises, simple devices), nutrition support and available antibiotics still transform outcomes.
• Pancreatic enzymes may be unavailable or unaffordable; optimise whatever is available, monitor stools and growth, and involve a dietitian.
• High-cost therapies such as CFTR modulators and lung transplantation are usually unavailable; the most cost-effective interventions are nutrition, airway clearance and prompt treatment of exacerbations.

• Cystic fibrosis is an autosomal recessive disease of the CFTR chloride and bicarbonate channel; severity follows roughly from mutation class.
• Loss of CFTR function dehydrates airway surface liquid, causing mucus plugging, chronic infection and progressive bronchiectasis.
• Incidence in European-descent populations is now 1 in 3,000 to 1 in 6,000; carrier rates are 1 in 28 to 1 in 40. ^[1]
• Newborn screening uses IRT followed by genetic testing; a positive screen is confirmed by sweat chloride and genotyping.
• Sweat chloride of 60 mmol/L or more is consistent with cystic fibrosis; 30 to 59 mmol/L is intermediate; under 30 mmol/L makes CF unlikely. ^[3]
• F508del (class II) causes about 70% of cystic fibrosis alleles worldwide. ^[3][5]
• Almost all males are infertile from obstructive azoospermia; CFRD affects up to 1 in 2 adults. ^[2]
• Chronic care combines airway clearance, rhDNase first, antibiotic prophylaxis and eradication, high-calorie diet with pancreatic enzymes, and monitoring of liver and bone.
• CFTR modulators improve function for eligible genotypes and can raise FEV1 substantially, but they do not replace conventional care.
• Modern median survival is close to 50 years, and adults are now the majority of patients. ^[1]

• Primary ciliary dyskinesia
• Bronchiectasis
• Malabsorption
• Chronic pancreatitis
• Liver cirrhosis and portal hypertension
• Type 1 diabetes mellitus
• Medical genetics: autosomal recessive inheritance
• Recurrent respiratory infections in children