Cystic Fibrosis

Cystic fibrosis is an autosomal recessive disease caused by a mutation in the CF transmembrane conductance regulator gene (CFTR) resulting in multisystem dysfunction. In 2022 the predicted mean life expectancy of a child born in 2022 was 56 years¹.

Epidemiology

Prevalence varies widely across populations, but broadly speaking, approximately 1 in 25 Caucasian Europeans are carriers of a CF gene with approximately 1 in 2500 live births having CF. p.Phe508del (ΔF508) is the commonest mutation in the UK with this accounting for at least one mutation in 90% of people with CF in the UK, with 50% of those with CF in the UK are homozygous for this mutation.¹

Pathophysiology

CF is a multisystem disease with over 350 recognised CF-causing mutations in the CFTR gene, from more than 2000 identified varients. Below we will discuss the basic underlying pathophysiology and complications of the disease:

Respiratory tract²

The CTFR gene encodes the CFTR protein – a chloride channel that is present in numerous epithelial tissues. Chloride is driven against its concentration gradient using ATP.

In the airway, CFTR is present on airway epithelial cells and submucosal glands and when defective results in disruption to chloride ion movement and also affects sodium reabsorption (by disturbing the function of ENaC) which reduces the amount of water in secretions. This results in reduced airway surface liquid.

The airway surface liquid is an important component of the mucociliary escalator and also has key immunological functions.  The effects of reduced airway surface liquid serve to impede mucus clearance.

The altered lung environment provides a niche for bacterial growth with the biofilm mode of growth providing ideal conditions to protect bacteria from the host immune system and the actions of antibiotics.  The pro-inflammatory cascade contributes to tissue damage.

https://www.cysticfibrosis.org.uk/sites/default/files/2024-06/UK%20CF%20Registry%20Highlights%20report%20for%202023%20annual%20data.pdf

Figure 1. Predicted FEV1% at annual review by age2

Pancreas

In the pancreas the pancreatic duct is usually occluded in-utero causing permanent damage to the exocrine pancreas rendering patients with CF ‘pancreatic insufficient’.  Pancreatic insufficiency is closely related to genotype.  Over time, endocrine pancreas is affected with 28% of those older than 10 years requiring treatment for CF-related diabetes mellitus.³

Gastrointestinal tract

In the gastrointestinal tract, the small intestine secretes viscous mucus which can cause bowel obstruction in-utero which can cause meconium ileus. In the biliary tree in-utero, CF can cause cholestasis which can result in neonatal jaundice.  Later in life the same pathology can result in distal intestinal obstruction syndrome (DIOS) and CF-related liver disease (14% of patients).

Reproductive tract

98% of men with CF are infertile due to a congenital absence of the vas deferens.  In women nutrition is likely to be an important predictor of successful pregnancy.  It is suggested that the timing of pregnancy be carefully planned, as pregnancy is often associated with a deterioration in lung health.

Risk Factors⁷

CF is an autosomal recessive condition. There are more then two thousand identified mutation for the CFTR gene that has been categorized into 5, or sometime 6, classes. They range from Class I mutation, a nonsense mutation, where a premature stop codon leads to no complete CFTR proteins being form, to Class V mutation where a complete CFTR protein is made and reaches the cell surface, but there’s deficency in number. p.Phe508del (ΔF508) is a class II mutation, in which misfolded proteins CFTR proteins are formed, of which most are degraded by the cell.

Different organs have different sensitivity to loss of CFTR protein function, with the vas deferens particularly sensitive in contrast to the lungs, which are less sensitive. Instead the lungs are more susceptible to other factors, like stochastic, environmental, and genetic modifiers-genes that modify the expression of CFTR protein.

Clinical Features and Diagnosis

Clinical Presentation⁵

Clinical presentation of CF can differ depending on the age at which patients present. The section below illustrates the usual ways in which children and young people with CF present at different periods in time.

• Neonates
  • Meconium ileus – 10% of children present with abdominal distension, delayed passage of meconium and bilious vomiting in the first days of life.
  • Since the introduction of screening for CF in neonates (part of the Guthrie test) the majority of cases of CF are identified here (however it is important to note that it is a screening test and still needs diagnostic testing)⁴
  • Failure to thrive
  • Prolonged neonatal jaundice
• Infancy
  • Failure to thrive
  • Recurrent chest infections
  • Pancreatic insufficiency: steatorrhoea
• Childhood
  • Rectal prolapse
  • Nasal polyps (N.B. strongly suspect CF in children presenting with nasal polyps)
  • Sinusitis
• Adolescence
  • Pancreatic insufficiency: diabetes mellitus
  • Chronic lung disease
  • DIOS, gallstones, liver cirrhosis

History

• The key aims of management of CF are early treatment of infection and optimisation of nutrition.
• In cases of poor adherence to treatment or late diagnosis the following may occur:
  • Productive cough that is either persistent or recurrent
  • Failure to thrive
  • Complaints of bowel symptoms; constipation, or pale, floating and offensive-smelling stools (steatorrhoea)
• Parents may report (less commonly) other symptoms
  • Rectal prolapse
  • Nasal polyps

Examination

Clinical examination may be entirely normal, variably and often related to the severity of lung disease. Some signs that may be elicited include:

• Hands: finger clubbing
• Face: nasal polyps
• Chest: hyperinflated, crepitiations, portacath (indwelling vascular access device)
• Abdomen: faecal mass (if constipated/DIOS), may have a scar from ileostomy (meconium ileus)

Investigations

Patients with cystic fibrosis will end up having a large number of investigations, partly directed by their clinical condition and also as standard routine monitoring of the disease. Standard investigations include:

• Chest radiograph: to assess for hyperinflation, there may be evidence of bronchial thickening (undertaken annually as part of annual assessment) Some units undertake CT scanning.
• Chloride sweat test (at diagnosis and annually if in receipt of CFTR potentiator/corrector therapy)
• Microbiological assessment e.g. cough swab/sputum sample (at every clinical encounter)
• Glucose tolerance test (at annual assessment at teenage and beyond)
• Liver function test and coagulation (at annual assessment)
• Bone profile (at annual assessment)
• Lung function testing – spirometry / lung clearance index

Additional investigations

• Faecal elastase to assess pancreatic function
• Chest CT (high resolution) to assess for bronchiectasis (where bronchial diameter would exceed that of accompanying pulmonary vessels)
• Genetic analysis to assess for one or more of the 32 commonly identified mutations. Interestingly, there may be no mutations identified in some cases however diagnosis is made by at least two positive sweat chloride tests and a suggestive clinical assessment.

Management

Given the multisystem nature of cystic fibrosis management is complex and is heavily reliant on a multidisciplinary team. To mention a few, a MDT would optimally include the patient’s GP, a respiratory paediatrician, a specialist CF nurse, a dietician, physiotherapist, psychologist and social worker.

The general aims of managing a child with CF include:

Patient and Family Education

• Clearly explaining diagnosis and providing written information and support information
• It is important that they understand it is a lifelong and life-limiting condition but can be managed but will require frequent follow-up

Airway Clearance and Chest Symptoms Management

• Usually twice-daily physiotherapy is needed. The rationale for physiotherapy is to increase airway secretion clearance which should reduce airway obstruction and minimise risk of infection
• Mucolytics and DNase
  • DNase (dornase alpha) is inhaled and reduces viscosity of mucus by digesting DNA which is abundant in the sputum of patients with CF
  • Hypertonic saline can aid airway clearance (and can be used at time of physiotherapy to further aid clearance)(limited evidence to support use in under 12 yrs).
• Bronchodilators are very useful and commonly used in conjunction with corticosteroids
• Oxygen supplementation is used in some patients (3.2%) which can range from non-invasive ventilation, nocturnal use or continuously

Modulator therapy

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene. Because different mutations cause different defects in the protein, the medications that have been developed since first used in 2012 are so far only effective in people with specific mutations. There are two main types of CFTR modulators: potentiators and correctors. Potentiators are CFTR modulators that hold the gate to the CFTR channel open so chloride can flow through the cell membrane. Correctors help the CFTR protein to form the right 3-D shape so that it is able to move — or traffic — to the cell surface.⁸

• Kalydeco = Ivacaftor has approval for use for people aged four months and older with at least one copy of a CFTR ‘gating’ mutation, and for people aged four months and over with the R117H.
• Orkambi = Lumacaftor/ivacaftor; is licensed for use in the UK for patients aged one and over with two copies of the F508del mutation.
• Symkevi = Tezacaftor/ivacaftor; is licenced for use in patients aged six and over who have two copies of the F508del mutation, or a single copy of F508del and one of 14 residual function mutations.
• Kaftrio = Elexacaftor/tezacaftor/ivacaftor; During 2022, elexacaftor/tezacaftor/ ivacaftor was available in the UK for patients with cystic fibrosis aged 6 and over who have two copies of the F508del mutation, or a single copy of F508del and one minimal function mutation. Guidance has been issued throughout the year from NHS commissioners across the devolved nations to support the prescribing of CFTR modulators “off-label”; this varies slightly across the devolved nations but covers the 177 mutations that are on an approved “FDA list”

Modulators have been shown to not only improve lung function, but also reduce antibiotic burden, BMI and sweat chloride levels⁹. They are generally well tolerated and are available as sachets of granules to be mixed with 5ml of soft food and consumed immediately, just before or after a fat-containing meal/snack. The most commonly used drug in the UK, Kaftrio, has shown an increased in lung function by 10%.¹⁰

Nourishment and Exercise

• All children with CF should be encouraged to undertake physical exercise and if symptoms are controlled most children will be able to perform equally as well to their peers
• For those patients who have pancreatic insufficiency they will need to have pancreatic enzyme supplementation (Creon) with meals which contain fats (should be taken at the start or during the meal)
• Fat-soluble vitamins (A, D, E and K) are poorly absorbed in those who have pancreatic insufficiency. Pancreatic enzyme replacement is not enough hence children with pancreatic insufficiency will also need to take vitamin A, D and E supplements. There is some debate as to whether vitamin K should be supplemented and this depends on different centres.
• Monitor growth
• Metabolic demands may be greater in patients with CF and so nutrition and growth are closely monitored to achieve optimal growth.
• Children with CF may have poor weight gain
  • Build-up milkshakes can be used to supplement meals (not in place of)
  • In extreme cases of malnutrition, poor weight gain may necessitate the need for supplemental enteral feeding (e.g. via a gastrostomy) and rarely the use of total parenteral nutrition

Managing/preventing airway infections

• Children with CF are predisposed to airway infection. Infections are prolonged and are characterised by host-neutrophil response
  • The common causative organisms include: Staphyloccocus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, and non-Tuberculosis mycobacteria
  • Patients with CF should have continual microbiological assessment to identify organisms colonised. Sputum cultures are preferable to cough swabs, but if a child cannot produce a sputum sample a cough swab will suffice acknowledging that a negative result may be falsely reassuring.
  • Infections should be treated with 2 weeks of antibiotics even if the child is asymptomatic and a repeat culture should be sent after treatment to ensure the infection is treated
• Pseudomonas aeruginosa infection in CF
  • Chronic infection is associated with poorer lung function hence it is important to detect and aggressively treat this infection
  • It is a common infection, and initially caused by an environmental strain that is eradicable. However chronic infection results in phenotype changes leading to colonies of Pseudomonas forming biofilms where they are protected from both host and antimicrobial attack. Hence when detected, an eradication regimen is employed.
  • Chronic Pseudomonas infections should be treated with inhaled antibiotics
• Antibiotics
  • All courses should be at least 2 weeks in length
  • High doses are needed to optimise sputum concentrations.
  • In the case of a symptomatic child empirical antibiotics informed from previous culture results may commence prior to the availability of current culture results.
  • Intravenous antibiotics may be needed to treat infections not responsive to oral antibiotics, or as part of some pseudomonas eradication regimens.
  • Prophylactic antibiotics are recommended to be used in infants until the age of 3 years.
  • Children with chronic Pseudomonas infection should be treated with long-term antibiotics to suppress Pseudomonas growth– these are often given as inhaled antibiotics
  • Regular azithromycin has been shown to reduce exacerbations and improve lung function even in those not chronically infected with Pseudomonas aeruginosa.
• Infection control
  • Active segregation serves to reduce cross-infection
  • Patients are cohorted such that ‘Pseudomonas naïve’ patients attend different clinics to those with chronic infection and those with non-tuberculous mycobacteria (NTM) attend a separate clinic.
  • Each patient will have their own clinic room which is cleaned and undergoes adequate air exchanges prior to the next patient.
  • When admitted each patient should be in a side-room

Other

• Minimising complications
• Monitoring the disease: Annual Review
  • At annual review the child would normally see a respiratory paediatrician, a dietician, physiotherapist and CF specialist nurse. During this review there should be a review of clinical symptoms, courses of antibiotics, a microbiological assessment, blood tests (FBC, renal function, liver function tests, vitamin A, D and E levels, clotting profile, HbA1c). Lung function tests should also be performed
  • A chest X-ray(CXR) is normally performed
  • Children aged 12 years or over will normally be investigated for CFRD by oral glucose tolerance test (OGTT).
•  Preparing for transfer to adult CF services during late adolescence

Complications

Again, due to multisystem nature of CF there are a number of complications that can arise.

Respiratory tract

• Allergic bronchopulmonary aspergillosis (ABPA) – an immune response to the prescence of Aspergillus spp. There are specific diagnostic criteria. ABPA can initially be treated with oral corticosteroids (prednisolone) and itraconzaole can also be tried
• Bronchiectasis
• Haemoptysis can occur
• Pulmonary hypertension and right heart strain
• Pneumothorax is a life-threatening complication occurring in up to 1% of older children with CF which is often associated with more advanced disease. Recurrence frequently occurs.
• Respiratory failure will eventually occur in patients with CF
• Nasal polyps can occur in up to 10% of children with CF which may be associated with sinusitis
• COVID-19 peaked with 2159 cases among all CF registered patients (11,319) in 2022 with 3.8% being hospitalised and 9 deaths¹. The pandemic also negatively impacted FC patients due to a reduction in review rates, access to spirometry, and longer isolation times.

Gastrointestinal tract

• Rectal prolapse can occur. The exact underlying mechanism is unknown but it is suggested that the frequent passage of bulky stools has a role. The first-line of management is to ensure the child has adequate pancreatic enzyme replacement and a laxative to minimise straining
• Distal intestinal obstruction syndrome (DIOS) is obstruction of the distal ileum and affects up to 10% of children with CF. It is suggested that DIOS results due to slower intestinal transit. The child would most likely present with colicky abdominal pain and clinical examination would reveal a palpable mass in the RLQ
• CF related liver disease
  • Cholestasis
  • Gallstones
  • Liver cirrhosis
  • Gastro-oesophageal reflux disease

Endocrine

• CF related diabetes (CFRD) is a serious complication and is associated with rapid decline in lung function and disease progression. It occurs in 5-10% of children with CF and is more common in older children with CF. Clinical presentation can differ to typical type 1 DM and comprises weight loss, anorexia and fall in lung function. Ketoacidosis is rarer in patients with CF as there is not an absolute lack of insulin. Children should be screened for CFRD at least yearly (>12 years) at annual review. Like conventional diabetes mellitus, children with CFRD should have annual retinopathy, hypertension and microalbuminuria screening.
• Delayed puberty is common in children with CF with an average delay of 2 years. Delayed puberty can have its own consequences e.g. reduced bone mineral density which predisposes children to fractures later in adolescence and adulthood.

Other

• Arthritis occurs in up to 10%
• Reduced bone mineral density
• Sub or infertility in later adolescence/adulthood
• Hearing loss (3.5%)
• Depression (5%)
• Transplant: On a decreasing trend and since 2020 has only been used in those >16 years of age¹

References

See also:

• Hull, J., Forton, J., & Thomson, A. H. (2015). Paediatric respiratory medicine. Oxford: Oxford University Press
• Lissauer, T., & Clayden, G. S. (2011). Illustrated textbook of paediatrics. Edinburgh: Mosby.