Cystic Fibrosis in Paediatrics

Cystic fibrosis (CF) is an autosomal recessive multi-organ disease caused by defects in a single gene, CFTR. The protein made by the CFTR gene helps control the movement of water, sodium, and chloride in and out of cells. Mutations in this gene can cause the production of thicker mucous, which affects many bodily systems.

Epidemiology

Prevalence: CF is most found in Caucasian individuals, especially Northern European.  It is less common in people of Asian, African, and Hispanic backgrounds.

Incidence: in the UK approximately 1 in 2500 to 1 in 3000 children have CF, and 1 in 25 are carriers.

Genetics

CF is caused by a mutation in the CFTR gene located on the long arm of chromosome 7. The CFTR gene is responsible for encoding the CFTR protein that is expressed mainly on the apical surface of epithelial cells of airways, gastrointestinal tract, sweat glands and the genitourinary tract.

More than 2000 polymorphisms have been described but those that are associated with clinical manifestations are grouped in to 6 main classes. Generally, class I-III are severe mutations whereas class IV-VI are associated with some residual function.

Classes of CFTR mutations Distribution of CFTR mutations into six functional classes 1

Figure 1: CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis – Sourced from ResearchGate.

The most common mutation in the UK (approx. 78%) is the delta-F508 (DF508), which is a class II mutation. This simply means that there is a deletion of a single phenylalanine residue at amino acid 508.

CF2

Since CF is inherited as an autosomal recessive trait, if both parents carry the faulty gene there’s a:

  • ¼ chance the child will have CF
  • ½ chance the child will be a carrier of CF, but not affected
  • ¼ chance the child is unaffected

Figure 2: Diagram to demonstrate inheritance of CF, sourced from CF News Today

Clinical Features

CF is a multi- system disease affecting the respiratory, gastrointestinal, endocrine and reproductive systems, and the sweat glands.

Respiratory:

Infants diagnosed from newborn screening will often be asymptomatic from a respiratory point of view for the first few months – year of life.

The earliest symptom is a cough, that persists unless treated with antibiotics, and this progresses to recurrent chest infections and bronchiectasis.

The most common pathogens found are Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa. These can colonise the respiratory tract and be very difficult to eradicate if not managed aggressively with IV antibiotics and physiotherapy when first found in the sputum or on a cough swab.

CF lung disease is characterised by a cycle of infection, inflammation, and damage. As lung disease progresses, chronic ‘wet’ cough, production of purulent sputum, deteriorating exercise intolerance and shortness of breath become more noticeable.

On examination you may find:

  • Chest hyperinflation due to air trapping:
    • Increased AP diameter of the chest.
    • Hyperresonance to percussion.
  • Coarse inspiratory crepitations and/or expiratory wheeze on auscultation
  • Lobectomy scars (lobar bronchiectasis can be managed with lobectomy).
  • Port-A-Cath may be palpable under the skin (used for IV access) or there may be a Hickmann line or PICC line in situ.
  • Finger clubbing: due to chronic hypoxia.
  • Nasal polyps.
CF3
CF4

Figure 3 and 4: CXR of a patient with CF lung disease, AP view (left) and lateral view (right). Figure 3 shows chest hyperinflation. On the lateral view (right) you can flattening of the hemidiaphragm and increased retrosternal space. There is onset of bronchiectasis on the upper lobes. Sourced from Medscape

Complications of CF lung disease:
  • Atelectasis,
  • Pneumothorax,
  • Cor pulmonale,
  • Allergic bronchopulmonary aspergillosis (ABPA),
  • Bronchiectasis,
  • Respiratory failure.
cystic fibrosis 2

Figure 5: CXR of a patient with advanced bronchiectasis. On the left side there is a Port-a-Cath, and tram track opacities are seen on both lungs, especially on the upper lobes.

Case courtesy of Frank Gaillard, Radiopaedia.org. From the case rID: 8247

Gastrointestinal:

15-20% of infants with CF present with meconium ileus:

  • Meconium ileus is a blockage of the terminal ileum with thick viscid meconium due to the mutation in the CFTR. The small intestine proximal to the blockage dilates with gas, meconium, and fluid.
  • This can be detected on antenatal scans, in which case there will be a plan for the baby following delivery, and they will usually be delivered in a centre that offers neonatal surgery.
  • Meconium ileus presents with abdominal distention, vomiting and failure to pass meconium in the first 24-48hrs of life.
  • Meconium ileus is a surgical emergency treated with a gastrografin enema, and delayed treatment can lead to meconium peritonitis, which requires surgery
CF6
meconium ileus 3

Figure 6(left): Abdominal X-ray of newborn with meconium ileus. The x-ray shows narrowing of the terminal ileum and distention of the proximal part of the intestine. Sourced from Learning Radiology Figure 7(right): Fluoroscopy of newborn with meconium ileus. Here you can see dilatation of the small bowel loops proximal to the obstruction, and filling defects at the ascending colon and distal ileum.Case courtesy of Ahmed Abdrabou, Radiopaedia.org. From the case rID: 24361

Ileal obstruction with faeces may occur in older children too. This is termed distal intestinal obstruction syndrome (DIOS).

  • DIOS causes cramping abdominal pain, distention, and obstruction.
  • Unlike meconium ileus, DIOS can be managed medically with laxatives (oral Gastrografin).

Over 90% of children with CF suffer with exocrine pancreatic insufficiency.

  • This means that the ability of the pancreas to excrete digestive enzymes (lipase, amylase, and proteases) is severely reduced resulting in maldigestion and malabsorption.
  • Without the proper nutrients, patients suffer from slow growth and failure to gain weight, whilst the fat malabsorption manifests as steatorrhea (passing of bulky, greasy pale stools), and deficiency of fat-soluble vitamins (A, D, E, K).
Endocrine:

In adolescents, progressive pancreas damage can lead to islet cell destruction causing insulin and glucagon deficiency. Initially, this presents as glucose intolerance, but over time this may develop into CF- related diabetes which would require insulin therapy.

Current UK guidelines (as of 2018) state screening for CF diabetes should begin from age 10 and be repeated annually. Frequent screening will aid early diagnosis and thus effective treatment, reducing the risk of the microvascular complications associated with diabetes. Current suitable methods for routine screening are the oral glucose tolerance test and continuous glucose monitoring.

Reproductive:

Men are usually infertile, whilst women suffer with reduced fertility. Reasons for infertility in men:

  • Obstructive azoospermia
  • Absent vas deferens
  • Undescended testicles

Reasons for reduced fertility in women:

  • Thicker cervical mucus obstructing fertilisation
  • Menstrual abnormalities

Both males and females may report delayed development of secondary sexual characteristics, but this is mostly related to malnutrition.

Sweat glands:

CF patients lose large amounts of sodium and chloride in their sweat, approximately 3-4 times more than those without CF as the gland is not able to absorb the salt back into the blood.

This predisposes young children to salt depletion episodes, especially with exercise, hot weather, fevers, and infections (gastroenteritis). Signs and symptoms of salt depletion to look out for include:

  • Fatigue
  • Irritability, headaches
  • Nausea and vomiting
  • Salt crystals on the skin, “salt frosting”
  • Muscle cramps
  • Hyponatraemia and hypochloraemic alkalosis

Presentation According to Age

The presentation of CF differs based on age, and can be summarised as:

NEONATESINFANTS AND TODDLERSYOUNG CHILDRENOLDER CHILDREN AND ADOLESCENTS
– Meconium ileus
– Prolonged neonatal jaundice (due to obstructive cholestasis)
– Hypoproteinaemia and oedema
– Faltering growth
– Recurrent chest infections
– Malabsorption, steatorrhea
– Salty skin (reported by parents when kissing the child)
– Recurrent chest infections
– Bronchiectasis
– Rectal prolapse
– Nasal polyps
– Sinusitis
– Malabsorption syndromes
– Faltering growth
– Recurrent chest infections
– Malabsorption syndromes
– Diabetes Mellitus
– Delayed onset of puberty
– DIOS
– ABPA

Diagnosis

In the UK, CF is screened for by the Guthrie test. The Guthrie test is commonly known as the neonatal heel prick blood spot test which is done in the first 5-7 days of life. The Guthrie test detects raised immunoreactive trypsinogen (IRT) which is indicative of CF with pancreatic exocrine insufficiency. This is not positive for every case of CF and therefore some children can go undiagnosed and present later in life.

Presence of any of the following requires further testing:

  • Positive newborn screen
  • First degree family member with CF
  • Typical features of CF (e.g., meconium ileus)

The gold standard to confirm CF is the sweat test.

  • The sweat test measures the amount of chloride in the sweat.
  • To cause sweating, pilocarpine is applied to a small area of the forearm or leg, and electrodes are placed over the area. A small current is applied, and sweat is collected into a capillary tube or filter paper over 30 minutes.
  • A chloride level > 60mmol/L is indicative for CF.
  • Confirmation of diagnosis can be made by repeating the sweat test, or by testing for CFTR mutations.

Genetic testing for mutations in the CFTR gene can be performed antenatally via amniocentesis or chorionic villous sampling, or after birth via blood tests.

At the time of diagnosis, it’s important to perform baseline investigations including FBC, U&Es, LFTs, vitamins ADEK, cough swab or sputum for microscopy and culture, aspergillosis IgE, and a CXR. These are then repeated routinely for monitoring, along with pulmonary function tests (PFTs), once the child is old enough:

  • PFTs: repeated every 3 months following diagnosis. Modality of choice is spirometry, and the common finding would be that of an obstructive pattern. (i.e., decreased FEV1: FVC ratio). Spirometry can only be performed in children from 4-5 years of age and older.
  • Imaging: chest x-ray or CT are indicated at diagnosis and every 2-4 years thereafter.
  • Microbiology: to look for pathogens, helping prevent and treat exacerbations. Sputum samples are most preferable, followed by cough swab or nasal pharyngeal aspirate.

Management of CF

Since CF is a multi-systemic disease, treatment is multifactorial. Treatment is split into maintenance therapies and exacerbation therapies. There are many aspects to maintenance therapies, which can be summarised according to systems:

Respiratory management:
  • Chest physiotherapy twice daily:  helps clear secretions and mucous from the airways and reduce risk of colonisation by pathogens. In younger children, this is accomplished by parents performing percussion and postural drainage, whilst older patients perform deep breathing exercises and use physiotherapy devices (flutter or acapella device).
W5522
Vol12No2 Bio Rek fig1

Figure 7 and 8: The flutter device, it uses positive expiratory pressure and oscillations to help clear the airway of sticky secretions. Sourced from the Biomedical and Pharmacological Journal, courtesy of Rekha K et al

  • Physical activity is beneficial as it improves respiratory reserve and function, thus is encouraged amongst all ages.
  • Nebulised mucolytics: DNase (Dornase Alfa) and hypertonic saline. Mucolytics effectively thin the mucus and make it easier to clear.
  • Bronchodilators: Short acting bronchodilators (SABA’s) aid in bronchodilation and may be used prior to inhaled therapies or chest physiotherapy.
  • Treating chest infections with 10-14 days of appropriate IV antibiotics.
  • Patients colonised with pseudomonas are often started on nebulised colomycin therapy for a minimum of 3 months to attempt to eradicate the bug.
  • In the UK, young children receive prophylactic oral flucloxacillin, until the age of 3 years, to reduce risk of bacterial infections, in particular S. aureus. There are currently studies reviewing the efficacy of this.
  • Up to date vaccinations: pneumococcal, influenza and varicella.

The only therapeutic option for end stage CF lung disease is bilateral lung transplantation.

Gastrointestinal management:

DIOS can be managed medically through several ways:

  • Gastrografin oral dose
  • Lactulose 1mL/kg/day
  • Oral acetylcysteine solution.
Nutritional Management:
  • Dietician input is always required in the management of CF.
  • High calorie diets and addition of nutritional supplements to compensate for malabsorption is required. In some cases, overnight feeding via gastrostomy is used. It is estimated that children with CF need 120-150% of normal energy intake.
  • Pancreatic insufficiency is treated with oral enteric coated pancreatic replacement therapy taken with all meals containing fat. These tablets are called CREON tablets, and they replace the missing lipase and proteases.
  • Supplementation of fat-soluble vitamins (A, D, E, K)
  • Treatment with insulin in cases of CF related diabetes.
  • Salt supplements: during the first year of life and summer months, salt depletion is of high risk therefore it is important to compensate for the losses.

Treatment of Exacerbations

Increased severity or new onset of symptoms can be a sign of pulmonary exacerbation. Exacerbations should be treated quickly and aggressively to prevent irreversible decline in lung function.

Signs of exacerbation may include increased coughing, sputum production, oxygen requirement and shortness of breath.

Antibiotic therapy may be challenging in CF patients due to antibiotic resistance. It is advised to prescribe initial antibiotics based on the sensitivities of the most recent routine sputum cultures, and adjust the antibiotics once results from new sputum cultures become available.

Since treatment should be quick, exacerbations require treatment in the hospital setting and an IV route should be established. IV antibiotics are usually given for 10-14 days, and courses may be finished at home depending on the condition of the child.

Most children with CF have a form of long-term IV access for managing exacerbations, such as a Port-A-Cath or Hickmann line.

CF9
CF10

Figure 9(left): Port-a-Cath, and its components. 1= portal chamber; 1a= silicone centre; 2= catheter. Sourced from Cystic Fibrosis Trust. Figure 10 (right): Port-A-Cath schematic. The Port-a-Cath is placed subcutaneously into a major vein, such as the jugular vein. It does not involve external tubing. Sourced from Centre for Clinical Haematology

CF11

Figure 11: Hickmann line. Unlike Port-a-Caths, Hickmann lines have external tubing that extends from the insertion site to the outside of the body. Sourced from Clinical Centre for Haematology

Health Professionals Involved

NICE guidelines recommend every patient with CF to be regularly reviewed by a multidisciplinary team at a specialist centre. How often routine reviews are depends on the age, and progression of lung disease of the patient. An example schedule outlined by NICE is shown below:

AgeFrequency
0-1 monthWeekly
1-12 monthsEvery 4 weeks
1-5 yearsEvery 6-8 weeks
5+ yearsEvery 8-12 weeks
AdultsEvery 3-6 months

 The MDT team should include the following members:

  • Specialist respiratory paediatrician
  • Specialist nurses
  • Specialist physiotherapist
  • Specialist dieticians
  • Specialist pharmacists
  • Specialist clinical psychologists

The MDT team should also include social workers to provide advice and support, not only to the patient, but their family members and carers too.

CFTR Modulators

Currently, four drugs are available on the NHS for CF: Kalydeco, Orkambi, Symkevi and Kaftrio. These drugs all belong to the class of CFTR modulators. CFTR modulator therapies are currently being developed to treat CF by targeting the origin of the disease, i.e., the different mutation classes. There are three classes of drugs that can alter the expression of CFTR: potentiators, correctors and amplifiers.

These CFTR modulators have been life changing for many CF patients and has infinitely improved quality of life for these patients. The main issue with CFTR modulators in children and adolescents is the same as with therapy and other medicines – poor compliance.

Potentiators, like ivacaftor (Kalydeco), allow the CFTR protein to function more effectively as a chloride channel. This drug is particularly helpful in patients with class III mutations (Gly551Asp) as it helps to improve pulmonary function and increases weight. Kalydeco was the first medicine for CF to become available on the NHS in December 2016 and it is available in the UK for patients over 4 months of age with one or more gating mutations.

Correctors, such as lumacaftor and tezacaftor, help the CFTR protein to fold correctly and get to the cell surface. Combination therapy with ivacaftor-lumacaftor (Orkambi) has been explored for patients who are homozygous for the F508del mutation. Currently, Orkambi is available for patients over 2 years old.

Symkevi is a combination of ivacaftor and tezacaftor. Symkevi is approved for patients who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and another mutation in the CFTR gene. In trials, patients who took Symkevi saw an average increase in FEV1. At present, children over the age of 6 are eligible to take this combination.

The newest drug approved for treating CF is called Kaftrio, it was made available to the NHS and UK patients in August 2020. Kaftrio is a triple combination therapy of two correctors (tezacaftor and elexacaftor) and one potentiator (ivacaftor). Elexacaftor and tezacaftor increase the number of CFTR proteins on the cell surface, whilst ivacaftor improves the activity of the CFTR protein. This helps make secretions less thick, thus helping relieve symptoms of the disease. Originally, the drug was licensed for use for patients age 12 and older with one F508del mutation + one function mutation, or two F508del mutations. However, a new deal agreed in January 2022 has approved Kaftrio eligible for children aged over 6 years old. Currently, there are clinical trials for the use of Kaftrio in ages 2-5.

CFTR amplifiers are relatively new class of drugs; they increase CFTR protein levels in cells and tissues thus increasing the substrates for other CFTR modulators; important to note is that amplifiers do not correct or improve the function of the CFTR protein by themselves. Amplifiers present in pre-clinical and clinical studies are PTI-428 and PTI-CH.

References

Alex Horsley, S. C. (2015). Cystic Fibrosis, 2nd ed, ORML. Oxford University Press.

Cystic Fibrosis Trust. (2022, November ). Retrieved from Management of cystic fibrosis diabetes: https://www.cysticfibrosis.org.uk/sites/default/files/2022-12/CF%20Diabetes%20Consensus%20FINAL_0.pdf

Jameson, F. K. (n.d.). Harrison’s principles of internal medicine, 20th ed. McGraw-Hill Eduction .

Karen K. Marcdante, R. M. (2023). Nelson Essentials of Paediatrics, 9th ed. Elsevier.

Lopes-Pacheco, M. (2023, September). Research gate. Retrieved from https://www.researchgate.net/figure/Classes-of-CFTR-mutations-Distribution-of-CFTR-mutations-into-six-functional-classes_fig5_307607531

NICE . (2017, October 25). Retrieved from Cystic fibrosis: diagnosis and management : https://www.nice.org.uk/guidance/ng78/chapter/Recommendations

Robert C Tasker, R. J. (2013). Oxford Handbook of Paediatics. Oxford University Press.

Tom Lissauer, W. C. (2022). Illustrated Textbook of Paediatrics, 6th ed. Elsevier.

Written by Nikhita Rathod, Final Year Medical Student at the Medical University of Varna, Bulgaria

Edited by Dr Rebecca Evans, Paediatric Registrar

How useful was this post?

Click on a star to rate it!

Average rating 0 / 5. Vote count: 0

No votes so far! Be the first to rate this post.

As you found this post useful...

Follow us on social media!

We are sorry that this post was not useful for you!

Let us improve this post!

Tell us how we can improve this post?

Related Posts

Autism
Autism Spectrum Disorder
Background Autism Spectrum Disorder (ASD) is a neurodevelopmental...
Cannula
Paediatrics: Venepuncture & Cannulation
This article will discuss how to take blood and cannulate patients...
Injury
Safeguarding History – The Basics
Children are vulnerable. Unfortunately, child abuse does happen,...

Leave a Comment

Your email address will not be published. Required fields are marked *

Follow us

Favourites

Newsletter

Trending Now

Understanding the MSRA
The Multiple Specialty Recruitment Assessment (MSRA) is a computer-based exam increasingly being used...
Passing the Prescribing Safety Assessment (PSA)
The PSA is aimed at final year medical students and those graduating overseas to assess their competency...
Resident Doctor's Pay Calculator 2024
We’ve created a pay calculator to help you better understand your salary, how much tax you’ll...
Paracetamol Overdose
Paracetamol overdose is a common presentation in A&E and so you may often find yourself looking after...
Prescribing IV Fluids
There are certain situations where you need to prescribe IV fluids which vary from fluid resuscitation...
Common Viral Infections (exanthem) in Paediatrics
Viral infections are extremely common in paediatrics and a common presentation to paediatric A&E is...
PICC Lines and Midlines
You may well be asked to take blood from a PICC line or be called to see a patient because their PICC...

Sign up for our awesome resources & exclusive discount codes!

Join 80,000+ users who have signed up for our free weekly webinars, referral cheat sheet, pay calculator & exclusive discount codes for Pastest, Quesmed, Medibuddy and many others!