Respiratory: Cystic Fibrosis & Primary Ciliary Dyskinesia

Question 1

What is cystic fibrosis (CF)?

Answer 1

Cystic fibrosis is an autosomal recessive disease caused by a mutation in the CF transmembrane conductance regulator gene (CFTR) resulting in multisystem dysfunction.

Question 2

How is CF inherited?

Answer 2

Autosomal recessive disease.

Question 3

What mutation is seen in CF?

Answer 3

Genetic mutation of the cystic fibrosis transmembrane conductance regulatory (CFRT) gene on chromosome 7.

Question 4

What % of Caucasian Europeans are carriers of a CF gene?

Answer 4

Approx 4% (1 in 25)

Question 5

What is the most common variant of the CFTR mutation in CF?

Answer 5

Delta-F508 mutation.

Question 6

Prevalence of CF?

Answer 6

1 in 2500 have CF

Question 7

What chromosome is the cystic fibrosis transmembrane conductance regulatory gene (CFTR) located on?

Answer 7

Chromosome 7

Question 8

What is the normal role of the CFTR gene?

Answer 8

Codes for CFTR protein –> a chloride channel.

This channel is found on epithelial surfaces.

Channel pumps Cl- into secretions –> this helps draw water into secretions –> thins secretions.

Question 9

What are the 3 consequences of the CF mutation?

Answer 9

1) Thick pancreatic and biliary secretions that cause blockage of the ducts, resulting in a lack of digestive enzymes such as pancreatic lipase in the digestive tract

2) Low volume thick airway secretions that reduce airway clearance, resulting in bacterial colonisation and susceptibility to airway infections

3) Congenital bilateral absence of the vas deferens in males. Patients generally have healthy sperm, but the sperm have no way of getting from the testes to the ejaculate, resulting in male infertility

Question 10

Both parents are healthy, one sibling has cystic fibrosis and a second child does not have the disease, what is the likelihood of the second child being a carrier?

Answer 10

We know the child doesn’t have the condition, so the answer is two in three.

Question 11

What does the CFTR gene encode?

Answer 11

Encodes the CFTR protein – a chloride channel that is present in numerous epithelial tissues.

Chloride is driven against its concentration gradient using ATP.

Question 12

Pathophysiology of CF in regard to the respiratory tract?

Answer 12

1) In the airway, CFTR (chloride channel) is present on airway epithelial cells and submucosal glands

2) When defective, this results in LESS chloride being pumped into secretions –> water cannot be drawn in (i.e. reduced airway surface liquid) –> thick secretions.

3) The airway surface liquid is an important component of the mucociliary escalator and also has key immunological functions.

4) The effects of reduced airway surface liquid serve to impede mucus clearance.

5) 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.

6) The pro-inflammatory cascade contributes to tissue damage.

Question 13

Pathophysiology of CF in regard to the pancreas?

Answer 13

In the pancreas the pancreatic duct is usually occluded in-utero causing permanent damage to the exocrine pancreas rendering patients with CF ‘pancreatic insufficient’.

Over time, endocrine pancreas is affected with 28% of those older than 10 years requiring treatment for CF-related diabetes mellitus.

Question 14

What causes pancreatic enzyme insufficiency in CF?

Answer 14

Thick pancreatic and biliary secretions cause blockage of the ducts, resulting in a lack of digestive enzymes such as pancreatic lipase in the digestive tract.

Question 15

What leaves CF patients susceptible to airway infections?

Answer 15

Low volume thick airway secretions that reduce airway clearance.

Question 16

What causes infertility in males with CF?

Answer 16

Congenital bilateral absence of the vas deferens.

Patients generally have healthy sperm, but the sperm have no way of getting from the testes to the ejaculate, resulting in male infertility.

Question 17

How can CF cause meconium ileus?

Answer 17

In the GI tract, the small intestine secretes viscous mucus which can cause bowel obstruction in-utero which can cause meconium ileus.

Later in life the same pathology can result in distal intestinal obstruction syndrome (DIOS).

Question 18

How can CF cause neonatal jaundice?

Answer 18

CF can cause cholestasis

Question 19

How can CF present in neonates?

Answer 19

1) Meconium ileus

2) Prolonged neonatal jaundice

3) Failure to thrive

Question 20

When are the majority of cases of CF picked up?

Answer 20

Heelprick test at birth.

Question 21

How does meconium ileus present?

Answer 21

• abdominal distension
• delayed passaage of meconium
• bilious vomiting in first days of life

Question 22

Clinical features of CF?

Answer 22

Neonates:
- meconium ileus
- prolonged neonatal jaundice
- failure to thrive

Infancy:
- recurrent LRTIs
- pancreatic insufficiency: steatorrhoea

Childhood:
- rectal prolapse
- nasal polyps (strongly suspect CF in children presenting with nasal polyps)
- sinusitis

Adolescence:
- pancreatic insufficiency: diabetes mellitus
- chronic lung disease e.g. bronchiectasis
- Distal intestinal obstruction syndrome (DIOS)
- gallstones
- liver cirrhosis
- pancreatitis (from blockage of pancreatic ducts)

Question 23

What causes nasal polyps in CF?

Answer 23

Thickened secretions in sinuses can lead to recurrent infection and subsequent nasal polyps due to chronic inflammation.

Question 24

How does distal intestinal obstruction syndrome (DIOS) present?

Answer 24

• bloating
• abdo pain
• vomiting

Question 25

Symptoms of CF?

Answer 25

• Chronic cough
• Thick sputum production
• Recurrent respiratory tract infections
• Loose, greasy stools (steatorrhoea) due to a lack of fat digesting lipase enzymes
• Abdominal pain and bloating
• Parents may report the child tastes particularly salty when they kiss them, due to the concentrated salt in the sweat
• Poor weight and height gain (failure to thrive)

Question 26

What signs may be seen in CF?

Answer 26

1) Low weight or height on growth charts

2) Nasal polyps

3) Finger clubbing (e.g. bronchiectasis)

4) Crackles and wheezes on auscultation

5) Abdominal distention

Question 27

How can a diagnosis of CF be made?

Answer 27

1) Fitting clinical history

2) Positive chloride sweat test

Question 28

There are three key methods for establishing a diagnosis of CF that you should remember for your exams.

What are they?

Answer 28

1) Newborn blood spot testing –> performed on all children shortly after birth and picks up most cases

2) Sweat test –> gold standard

3) Genetic testing for CFTR gene –> can be performed during pregnancy by amniocentesis or chorionic villous sampling, or as a blood test after birth

Question 29

What happens in the sweat test for CF?

Answer 29

1) Pilocarpine is applied to a patch of skin.

2) Electrodes are placed either side of the patch and a small current is passed between the electrodes.

3) This causes the skin to sweat.

4) The sweat is absorbed with lab issued gauze or filter paper and sent to the lab for testing for the chloride concentration.

5) Increased chloride –> CF

Question 30

What is the diagnostic chloride concentration for cystic fibrosis?

Answer 30

> 60 mmol/l

Question 31

Relevant bedside investigations in CF?

Answer 31

1) Urine dip: for glucose in case of diabetes

2) Lung function testing: an obstructive picture is most common but can be restrictive, mixed or normal

Question 32

Relevant lab investigations in CF?

Answer 32

1) Bloods:
- FBC and CRP (infection and anaemia)
- U&Es
- fasting glucose
- LFTs (biliary or liver effects)
- vitamin A, C and E levels

2) Sputum culture and sensitivity

3) Sweat testing: high chloride concentration

4) Genetic testing: for CFTR

5) Faecal elastase: for pancreatic insufficiency

Question 33

Relevant imaging investigations in CF?

Answer 33

1) CXR:
- bronchiectasis
- hyperinflation

2) High-resolution CT chest:
- bronchial wall thickening
- bronchiectasis (tree-in-bud appearance, signet ring sign)
- mucus plugging (finger in glove)

3) CT angiography: in haemoptysis, if endovascular intervention is being considered

Question 34

What are 6 bacteria that commonly cause respiratory infections in CF?

Answer 34

1) Staphylococcus aureus

2) Haemophilus influenza

3) Klebsiella pneumoniae

4) Escherichia coli

5) Burkhodheria cepacia

6) Pseudomonas aeruginosa: this is a particularly troublesome coloniser as is hard to treat and worsens the prognosis of patients with CF.

Question 35

What prophylactic Abx do patients with CF take long term to prevent staph. aureus infections?

Answer 35

flucloxacillin

Question 36

Why can colonisation with pseudomonas lead to a significant increase in morbidity and mortality in patients with CF?

Answer 36

Once patients become colonised with pseudomonas, it can be very difficult to get rid of. Often, these bacteria can become resistant to multiple antibiotics.

The general advice is now to avoid contact with other children with CF.

Question 37

What can pseudomonas colonisation be treated with in CF?

Answer 37

Long term nebulised antibiotics such as tobramycin. Oral ciprofloxacin is also used.

Question 38

What does the management of CF involve?

Answer 38

1) Patient & family education

2) Airway clearance & chest symptoms management

3) Nourishment & exercise

4) Managing/preventing airway infections

5) Monitoring the disease

Question 39

What is involved in the management of respiratory manifestations in CF?

Answer 39

1) Twice-daily chest physiotherapy: to increase airway secretion clearance to reduce airway obstruction and minimise risk of infection.

2) Prophylactic antibiotics and antibiotics for acute exacerbations.

3) Inhaled bronchodilators

4) Mucolytics (oral or inhaled): hypertonic saline or dornase alfa

Question 40

What is the role of DNase (dornase alpha) in CF?

Answer 40

DNase (dornase alpha) is inhaled and reduces viscosity of mucus by digesting DNA which is abundant in the sputum of patients with CF.

Question 41

What is the role of hypertonic saline in CF?

Answer 41

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).

Question 42

How is pancreatic insufficiency in CF usually managed?

Answer 42

Pancreatic enzymes (Creon)

Question 43

What does management of nourishment & exercise involve in CF?

Answer 43

1) Encouraged to undertake physical exercise

2) Pancreatic enzyme supplementation (Creon) with meals which contain fats (should be taken at the start or during the meal)

3) Vitamin A, D and E supplements

4) Monitor growth

5) Children with CF may have poor weight gain:
- Build-up milkshakes can be used to supplement meals (not in place of)
- May be necessary to have supplemental of enteral feeding (e.g. via a gastrostomy)

Question 44

What are the fat soluble vitamins?

Answer 44

A, D, E and K

Question 45

Why do patients with CF with pancreatic insufficiency require vitamin A, D and E supplements?

Answer 45

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.

Question 46

How long should all courses of Abx in CF last?

Answer 46

2 weeks.

Question 47

What is the mainstay of surgical management of CF?

Answer 47

Transplant (lung +/- heart).

Question 48

Respiratory complications of CF?

Answer 48

1) Bronchiectasis

2) Recurrent infections

3) Cor pulmonale from pulmonary HTN and right heart strain

4) Haemoptysis (can be large volume and life-threatening)

5) Pneumothorax

6) Nasal polyps

7) Respiratory failure will eventually occur

8) Allergic bronchopulmonary aspergillosis (ABPA)

Question 49

What is allergic bronchopulmonary aspergillosis (ABPA)?

Answer 49

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.

Question 50

What can ABPA initially be treated with?

Answer 50

Oral prednisolone

Question 51

What are the GI complications of CF?

Answer 51

1) Rectal prolapse (from frequent passage of bulky stools)

2) Distal intestinal obstruction syndrome (DIOS)

3) CF related liver disease:
- Cholestasis
- Gallstones
- Liver cirrhosis

Question 52

What are the endocrine complications of CF?

Answer 52

1) CF related diabetes

2) Delayed puberty –> can result in reduced bone mineral density which predisposes children to fractures later in adolescence and adulthood.

Question 53

What is primary ciliary dyskinesia (PCD)?

Answer 53

It is an autosomal recessive condition affecting the cilia of various cells in the body.

PCD causes dysfunction of the motile cilia around the body.

Question 54

What is PCD also known as?

Answer 54

Kartagener’s syndrome

Question 55

How is Kartagener’s syndrome inherited?

Answer 55

Autosomal recessive

Question 56

What does Kartagener’s syndrome have a strong association with?

Answer 56

Consanguinity (meaning the parents are related to each-other).

Consanguinity increases the risk of a child having two copies of the same recessive genetic mutation.

Question 57

what organs does Kartagener’s syndrome affect?

Answer 57

1) Lungs –> dysfunction of the motile cilia in the respiratory tract leads to a buildup of mucus in the lungs. This leads to a similar respiratory presentation to cystic fibrosis, with frequent and chronic chest infections, poor growth and bronchiectasis.

2) Affects the cilia in the fallopian tubes of women and the tails (flagella) of the sperm in men –> reduced or absent fertility.

Question 58

What is Kartagner’s triad?

Answer 58

Kartagner’s triad describes the three key features of PCD. Not all patients will have all three features.

1) Paranasal sinusitis

2) Bronchiectasis

3) Situs inversus

Question 59

What is situs inversus?

Answer 59

A condition where all the internal (visceral) organs are mirrored inside the body. Therefore the heart is on the right, the stomach is on the right and the liver is on the left.

Dextrocardia is when only the heart is reversed.

Question 60

What % of patients with situs inversus will have PCD?

Answer 60

25%

Question 61

What % of patients with primary ciliary dyskinesia have situs inversus?

Answer 61

50%

Question 62

Features of Kartagener’s syndrome?

Answer 62

1) dextrocardia or complete situs inversus

2) bronchiectasis

3) recurrent sinusitis

4) subfertility (secondary to diminished sperm motility and defective ciliary action in the fallopian tubes)

Question 63

How do patients with Kartagener’s syndrome typically present?

Answer 63

Patients typically present with recurrent respiratory tract infections

Question 64

Investigations in Kartagener’s syndrome?

Answer 64

1) Careful FH and history of consanguinity in the parents

2) Investigations for situs inversus e.g. CXR

3) Semen analysis: male infertility

4) Take a sample of the ciliated epithelium of the upper airway and examine the action of the cilia.

Question 65

What is the key investigation for establishing the diagnosis of PCD?

Answer 65

Take a sample of the ciliated epithelium of the upper airway and examine the action of the cilia –> sample can be obtained through nasal brushing or bronchoscopy.

Question 66

2 options for obtaining sample of the ciliated epithelium of the upper airway in PCD?

Answer 66

1) nasal brushing

2) bronchoscopy

Question 67

Management of Kartagener’s syndrome?

Answer 67

Management is similar to cystic fibrosis and bronchiectasis with daily physiotherapy, a high calorie diet and antibiotics.

Question 68

How can CF present in neonates?

Answer 68

Meconium ileus –> surgical emergency.

1st stool of neonates (the meconium) is so thick and sticky that it gets stuck in intestines.

Question 69

What is the most prominent effect of CF in early childhood?

Answer 69

Pancreatic insufficiency

Question 70

Cause of pancreatic insufficiency in CF?

Answer 70

Thick secretions block pancreatic duct –> digestive enzymes can’t make it to small intestine.

Question 71

Effects of pancreatic insufficiency in CF?

Answer 71

1) Lack of digestive enzymes means that fats and proteins are poorly absorbed –> poor weight gain & failure to thrive.

2) Steatorrhoea (fatty stools).

3) Eventually results in pancreatic damage (as backed up pancreatic enzymes degrade the cells that line the ducts).

4) Acute or chronic pancreatitis (development of cysts & fibrosis)

5) Can result in insulin dependent diabetes

Question 72

What are 2 problematic bacteria in lung problems in CF?

Answer 72

1) Staph. aureus (gram +ve)

2) Pseudomonas aeruginosa (gram -ve)