Cystic fibrosis is the most common autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, encoding for a chloride channel in the cell membranes of exocrine glands. The most common mutation is Delta F508 (ΔF508 mutation) on chromosome 7, resulting in altered chloride transport and water flux across the apical membrane of epithelial cells. Cystic fibrosis is a multi-system disorder as it affects the respiratory, gastrointestinal, urogenital and musculoskeletal system. In the majority of cases, cystic fibrosis is diagnosed based on clinical features, a positive genetic test or a positive sweat chloride test. There is currently no cure for cystic fibrosis and patients are managed symptomatically with bronchodilator therapy and chest physiotherapy. The leading cause of death are the complications of advance lung disease.

Cystic fibrosis is a hereditary autosomal recessive disorder resulting in the defective CFTR protein as a result of the CFTR gene mutation. Patients can be either homozygous or heterozygous with respect to CFTR mutations.

• The most common mutation is Delta F508 (ΔF508 mutation) on chromosome 7
• Symbolises the lack of phenylalanine (F) in position 508 of the CFTR protein.

It is important to note that carriers of one normal CFTR allele and one of the CFTR mutations typically do not demonstrate clinical manifestations of cystic fibrosis.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome 7, translates into a chloride channel on the cell membranes of exocrine glands. The mutated CFTR gene results in a defective protein and subsequently the chloride channel is absent on the cell membrane of epithelial cells of exocrine glands. This subsequently leads to depletion of the airway surface liquid necessary for the cilia in the lungs. The decreased ciliary function has as a consequence the vicious cycle of mucous retention leading to chronic infections and inflammation.

With respect to the underlying pathophysiological mechanism consider the following two categories of exocrine glands.

All exocrine glands (except sweat glands)

• Normal physiological process: the chloride channel is secreting chloride out of the cell and into the lumen.
• Mutated CFTR gene in cystic fibrosis: with a defective chloride channel there is a reduction of chloride excretion into the lumen of the exocrine gland and an increase water and sodium reabsorption.
• Defective chloride channel → ↓ chloride excretion and ↑ water and sodium reabsorption → accumulation of thick and viscus mucus → blockage of exocrine glands in the affected organs (e.g. lungs and pancreas) → chronic inflammation and organ damage.
• Specifically in the lungs: blocked exocrine glands → retention of mucus → chronic respiratory infections and inflammation → chronic respiratory disease.
• Specifically in the pancreas: blocked exocrine glands → activation of pancreatic enzymes → autodigestion of the exocrine pancreas.

Sweat glands

• Normally physiological process: the chloride channel is responsible for the reabsorption of chloride into the cell.
• Mutated CFTR gene in cystic fibrosis: with a defective chloride channel, the chloride cannot be reabsorbed into the sweat glands leading to high levels of chloride in sweat and reduced absorption of water and sodium.
• Defective chloride channel → ↓ chloride reabsorption and ↓ absorption of water and sodium → ↑ levels of chloride in sweat (sweat chloride test).

Every baby that is born in the UK usually has the newborn blood spot test on day 5 of his/her life according to the newborn blood spot screening programme. One of the 9 rare genetic conditions that is screened with the blood spot test is cystic fibrosis. A positive blood spot test for cystic fibrosis is not necessarily diagnostic and every child needs to be referred to a cystic fibrosis specialist clinic for further investigations as it is described below. The majority of children with cystic fibrosis most commonly present via this pathway.

In the case of an infant child, the primary sign of CFTR dysfunction is the gastrointestinal tract with the presentation of symptomatic meconium ileus, a form of intestinal obstruction, that usually presents prior to the results of the newborn screening test.

In an older child, the most common clinical features that lead to the diagnosis of cystic fibrosis are:

• Chronic cough
• Recurrent wheezing
• Chronic respiratory infections
• Malabsorption in the gastrointestinal tract
• Failure to thrive

As it has been described above cystic fibrosis can present with an array of signs and symptoms and in order to better understand them it is easier to categorise them into organ systems, e.g. respiratory, gastrointestinal etc.

Respiratory effects

Respiratory symptoms are more common in adulthood rather than childhood, however cystic fibrosis is the commonest cause of recurrent bronchopulmonary infections in children.

• The majority of children tend to suffer from:
  • Airway hypersensitivity (e.g. wheeze)
  • Chronic respiratory tract infections
  • Chronic sinusitis
  • Nasal polyps
• As the patients grow older they are more prone to eventually develop:
  • Breathlessness due to obstructive lung disease
  • Haemoptysis as bronchiectasis develops and there is an airflow limitation
  • Respiratory failure
  • Cor pulmonale
• It is very important to acknowledge some characteristic microorganisms that cause recurrent pulmonary infections and chronic productive cough in cystic fibrosis patients.
  • During infancy and childhood Staphylococcus aureus is predominant.
  • During adulthood Pseudomonas aeruginosa is more common.

Gastrointestinal effects

The gastrointestinal tract is the second most common organ system that is affected in cystic fibrosis.

• Newborns are usually born with meconium ileus (8% of infants) due to the increased viscosity of the meconium, i.e. the first passage of stools.
• Almost all the patients with cystic fibrosis suffer from exocrine pancreatic insufficiency which can manifest in the form of:
  • Foul-smelling steatorrhea (fatty stools)
  • Malabsorption
  • Diarrhoea
  • Abdominal distention
  • Deficiency of fat-soluble vitamins.
• It is also common in adulthood that patients might develop CF-related diabetes mellitus or chronic pancreatitis.
• Cystic fibrosis can also affect the liver and biliary tract system, that can manifest as:
  • Cholecystolithiasis
  • Cholestasis
  • Biliary cirrhosis with portal hypertension.

Urogenital effects

The urogenital tract of cystic fibrosis patients is the third most common organ system that is affected.

• Patients usually suffer from a variety of urological problems.
  • Frequent urinary tract infections
  • In a lesser extent nephrolithiasis and nephrocalcinosis.
• Males are almost always infertile usually due to the absence of the vas deferens and epididymis resulting in obstructive azoospermia, a characteristic feature of cystic fibrosis.
• In females the increased viscosity of the cervical mucus can obstruct fertilisation but they are able to conceive.
• As the disease progresses, females suffer from menstrual abnormalities and often develop secondary amenorrhoea.
• Both sexes have delayed secondary sexual development.

Other effects

Many cystic fibrosis patients suffer from nutritional deficiencies and therefore it is crucial that cystic fibrosis patients have a high-calorie diet with supplementation of vitamins and nutrients as poor nutrition is associated with high rates of pulmonary sepsis. Some examples include:

• Malnutrition due to maldigestion and malabsorption
• Deficiency of fat-soluble vitamins
  • Night blindness due to vitamin A
  • Rickets due to vitamin D

In the majority of cases, suspected cystic fibrosis is based on clinical features, a positive newborn screen or from another family member with cystic fibrosis. The 2017 NICE guidelines [NG78] recommend that the initial investigations to order are firstly the sweat test, secondly the immunoreactive trypsinogen (IRT) test and finally genetic testing.

• Sweat test
  • Can be performed both in children and adults.
  • The most conclusive diagnostical test for cystic fibrosis.
  • Pilocarpine is used to induce sweating and once collected, the sweat chloride concentration is measured and compared to the normal ranges.
  • Two tests are required to be performed in two different days from an experienced laboratory.
  • A positive sweat test is considered if the sweat chloride level is > 60 mmol/L and requires urgent referral to a cystic fibrosis clinic.
  • A sweat chloride level of < 30 mmol/L is considered negative in all age groups.
  • If a sweat test results falls in between the two values, further investigations might be necessary.
• Immunoreactive trypsinogen (IRT) test
  • The IRT is the first screening tool and is part of the newborn screening assay.
  • A positive IRT test is not diagnostic of cystic fibrosis and all patients need to be referred to a cystic fibrosis clinic for further investigations.
• Genetic testing
  • Genetic testing can be done either as a primary screening test or as part of confirmation of a positive IRT result or negative sweat test in patient with suspected cystic fibrosis.
  • The laboratory will screen for the most common cystic fibrosis transmembrane conductance regulator (CFTR) mutations such as ΔF508.

Additional investigations to consider

• Blood tests (FBC, U&E, LFTs etc) might show contraction alkalosis and hypokalaemia due to the disproportionate loss of NaCl and H2O from the sweat glands and kidneys.
• A chest x-ray or CT scan may be performed showing evidence of hyperinflation and/or bronchiectasis.
• Pulmonary function tests can also be performed and result in findings consistent with an obstructive respiratory picture.
• An ultrasound scan of the liver might show increased echogenicity indicating a fatty liver consistent with cystic fibrosis.

Cystic fibrosis can be diagnosed based on the three following situations according to 2017 NICE guidelines [NG78]:

• A child or young adult with no symptoms but with a positive test results, for example blood spot immunoreactive trypsin test (infant screening) followed by sweat chloride and gene test for the confirmation of the result.
• A child or young adult with clinical features of cystic fibrosis, confirmed by sweat chloride or gene test results.
• A child or young adult with solely clinical features of cystic fibrosis, in the rare case where sweat chloride or gene test results are normal.

The typical clinical features of cystic fibrosis include: chronic respiratory infections and obstructive lung disease, gastrointestinal and nutritional abnormalities as well as obstructive azoospermia.

It is however very important that a child or a young adult that fits into one of three situations above is referred to a specialist cystic fibrosis centre.

Although cystic fibrosis has some characteristic features it always important to exclude some other conditions that might present in the same way. The main differentials that a doctor should consider are:

• Asthma
• Primary ciliary dyskinesia
• Primary immunodeficiency

Below you will find a table explaining the key differences in signs and symptoms of these conditions with cystic fibrosis and what investigations should a doctor consider order to exclude these conditions.


Primary ciliary dyskinesia (PCD)

• PCD is an autosomal recessive genetic disorder, which is characterised by:
  • Chronic respiratory infections
  • Chronic otitis media
  • Infertility
  • Abnormally positioned internal organs (50% suffer from situs inversus totalis)
• The majority of babies with PCD present with breathing difficulties at birth and develop frequent respiratory infections.
• Children with PCD are usually diagnosed with the use of genetic testing.
• Currently, there are no available treatments to cure the disease and the management of PCD surround symptom and complication management, with the administration of antibiotics and the use of chest physiotherapy

Primary immunodeficiency (PI)

• PI encompasses a group of different disorders that primarily affect the immune system development and function.
• There are over 400 types of PI, which vary in severity, with the most severe being: severe combined immunodeficiency (SCID)
• Signs and symptoms:
  • Frequent respiratory, sinus, ear and skin infections
  • Failure to thrive
  • Abdominal pain, diarrhoea or constipation
• PI is diagnosed based on genetic testing
• Treatment is usually supportive in the form of antibiotic prophylaxis and with definitive gene therapy in a minority of PI types

Cystic fibrosis is a genetic disease with no available cure. According to 2017 NICE guidelines [NG78], cystic fibrosis is managed by offering airway clearance techniques, chest physiotherapy, early start of antibiotics for respiratory infections, nutritional supplements and regular monitoring. In order to fully comprehend the management options of cystic fibrosis it is better to consider them according to the different organ systems affected.

Respiratory Support

In order to effectively manage the respiratory complications of cystic fibrosis patients, someone should consider chest physiotherapy, prescribing prophylactic antibiotics and mucolytics.

• Patients with cystic fibrosis and their carers should be educated and trained on airway clearance techniques.
• Chest physiotherapy should be offered in all patients.
  • Chest physiotherapy works by shifting the position of the mucus that has been built up in the airways and therefore assisting in its clearance.
  • It is usually performed twice a day and the difference techniques are usually adjusted to the patient's age and physical activity.
• Patients that have clinical signs of respiratory disease should be started on nebulised mucolytic agents (such as dornase alfa) or hypertonic saline nebulisation.
  • Nebulised dornase alfa has the ability to cutting the long DNA strands of white blood cells into shorter strands and therefore breaking up the thick mucus produced by them.
  • Nebulised hypertonic saline works by increasing the amount of sodium and therefore water into the airways and effectively thinning the mucus.
• Patients might benefit from bronchodilator therapy such as short-acting beta-2 agonists (SABA).
• Cystic fibrosis patients suffer from chronic respiratory infections and they should be given antibiotic prophylaxis.
  • Children should receive flucloxacillin as prophylaxis for Staphylococcus aureus infection
  • Adults with repeated respiratory infections should be offered long-term azithromycin treatment.
• Patients should also receive the annual influenza vaccine and pneumococcal vaccine .
• Patients with advanced respiratory disease should be investigated for hypoxaemia and should be consider for long-term oxygen inhalation therapy if oxygen saturations are low.
• In patients with very advanced and irreversible respiratory damage lung transplantation might be consider as treatment of last resort.

Nutritional Support

Cystic fibrosis patients usually suffer from malnutrition and pancreatic insufficiency and therefore nutritional support is vital for their survival.

• Patients should follow a high-calorie, high energy and nutrient-dense diet as many infants with cystic fibrosis suffer from poor height and weight growth.
• Patients should also receive supplementation of lipid soluble vitamins (vitamin A, D, E and K) as they are essential for their normal growth.
• As patients with cystic fibrosis get older they suffer from pancreatic insufficiency and they are unable to produce pancreatic enzymes, therefore pancreatic enzyme supplements are necessary for them to be able to digest food properly

CFTR Modulator Therapy

A rather new class of drugs for managing cystic fibrosis is CFTR modulators (e.g. Ivacaftor) that have been proven to be an important advancement in the management of cystic fibrosis.

• CFTR modulators target the production and function of defective CFTR proteins.
• CFTR modulators bind and open the defective chloride channel at surface of the epithelial cell by regulating the amount of fluids on its surface and therefore decreasing the thick mucus accumulation.
• CFTR modulators can only be used on certain mutations of the CFTR gene (e.g. G551D mutation)
• CFTR modulator efficacy depends upon the CFTR mutations in an individual patient, so they can only be used in a limited amount of patients
• The effects of CFTR modulators are usually evident only when the bioavailability of the drug remains over a specific level, therefore the medication needs to be taken on daily regular intervals.
• As with all medications, CFTR modulators have some minor adverse effects:
  • Abdominal pain
  • Diarrhoea
  • Dizziness

Monitoring

It is essential that cystic fibrosis patients have regular respiratory monitoring in a specialist centre.

• In children the routine review should be every 8 weeks.
• In adults the routine review should be every 3 months.

In each review, the following assessments should be carried out:

• A detailed clinical assessment with history and examination
• Lung function tests with spirometry
• Sputum samples should be sent for microbiological investigations
• Blood tests (e.g. FBC, U&Es, LFTs, lipase etc) may be ordered according to the patient's symptoms and progression of the disease
• Chest x-ray and CT scan may be ordered according to the patient's symptom and progression of the disease
• Nutritional assessment and exocrine pancreas function
• Look for signs and symptoms of complications, such as liver disease, cystic fibrosis related diabetes, osteoporosis etc.

Finally, it is very important that all patients are reviewed annually by a specialist clinical psychologist for a psychological assessment and providing any necessary additional help.

Cystic fibrosis complications can be divided into three categories according to their likelihood of happening.

High likelihood

• Delayed puberty: affecting both males and females
• Failure to thrive: resulting from the increased caloric demands
• Chronic sinusitis: usually all patients with cystic fibrosis have opacified sinuses on x-ray
• Chronic respiratory acidosis: commonly seen in advanced lung disease
• Meconium ileus: distal small bowel obstruction in neonates due to failure to pass meconium. Presents with abdominal distention, bilious vomiting and failure to pass meconium
• Infertility: almost all male patients with cystic fibrosis are infertile due to obstructive azoospermia. Female patients have reduced fertility.

Medium likelihood

• Acute respiratory failure: commonly seen in advanced lung disease with hypercapnia and hypoxaemia during a respiratory exacerbation
• Cor pulmonale: the majority of patients with chronic hypoxaemia and hypercapnia will suffer from right ventricular hypertrophy
• Cystic fibrosis- related diabetes mellitus
  • Constitutes a combination of both type 1 and type 2 diabetes.
  • Prevalence increases with age and it usually affects 50% of the adult population with cystic fibrosis.
  • Patients may experience microvascular complications but macrovascular complications are rare.
• Short stature
  • The nutritional status of cystic fibrosis patients should be monitored from early infancy as poor nutritional support is associated with decreased lung function.
  • Diet usually constitutes of high caloric-dense foods.
• Osteoporosis: commonly seen equally in both men and women and may result from:
  • Delayed puberty
  • Low physical activity
  • Steroid usage
  • Malnutrition
  • Chronic inflammation
• Depression and anxiety: commonly seen in cystic fibrosis patients starting from adolescence and contributing to:
  • Decreased adherence
  • Low body mass index
  • Low quality of life
• Rectal prolapse: seen in the first 3 years of life and usually in undiagnosed patients.
• Nasal polyps: often seen in patients with cystic fibrosis
• Distal intestinal obstructive syndrome: a minority of patients might experience a partial or complete obstruction of the terminal ileum
• Drug-related hearing loss: a common side-effect of IV aminoglycosides (e.g. gentamicin) and vancomycin used to treat respiratory infections.
• Drug-related nephrotoxicity: a common side-effect of IV aminoglycosides (e.g. gentamicin) used to treat respiratory infections.

Low likelihood

• Constipation: increased bulk of stools in pancreatic-insufficient cystic fibrosis patients leads to high risk of constipation.
• Acute/recurrent pancreatitis: occurs most commonly in older patients with the accumulation of pancreatic secretions due to obstructions in the pancreatic duct and pancreatic autodigestion by pancreatic enzymes.
• Intussusception
  • Usually seen in school-aged children and adolescents.
  • Commonest intussusception is the ileocolic
• Allergic bronchopulmonary aspergillosis (ABPA)
  • Hypersensitivity reaction to Aspergillus fumigatus colonisation of the lung
  • Characterised by wheezing, high IgE and aspergillus-specific IgG and centrally located infiltrates on chest x-ray.
• Pneumothorax: commonly seen with advanced lung disease
• Pulmonary hypertrophic osteoarthropathy: usually seen after the age of 12 with the manifestation of swelling and pain at the distal end of the long bones of the arms and legs
• Advanced liver disease: most common non-respiratory cause of death in cystic fibrosis
• Metabolic alkalosis: low incidence with early detection of cystic fibrosis
• Arthritis: transient knee arthritis is commonly seen
• Rickets: seen due to nutritional deficiencies but low incidence as monitored frequently

Cystic fibrosis is a genetic disease with no available cure. However, the mean age survival age has significantly improved from infancy to almost 40 years old.

• The key determinant of life expectancy is the severity of lung disease
• The longevity of patients with cystic fibrosis is due to the combined efforts of: clinicians, scientists, families, carers and foundations that have established together worldwide progress in the medical and psychological management of cystic fibrosis patient care.
• Death usually occurs as a result of:
  • Chronic respiratory failure
  • Cor pulmonale
  • From respiratory complications such as pneumothorax or pneumonia.