Cystic Fibrosis E-book

Question 1

What is CF

Answer 1

alteration in the viscosity and tenacity of mucus produced at epithelial surfaces

Question 2

The CFTRP is found in

Answer 2

The CFTRP is found in the epithelial cells of the lungs, pancreas, intestine, gall bladder, salivary and sweat glands, testes and uterus, thus CF is a multisystem disorder.

Question 3

Diagnosis

Answer 3

 Clinical history
 Symptoms
 Family history
 Sweat test
 DNA analysis of gene defect
 Radiology
 Absent vas deferens and epididymis
 Trypsinogen test
 Other testing investigations as appropriate

Question 4

Gastrointestinal system - how does CF affect

Answer 4

 Thick mucus secretions can cause blockage of the GI tract
 Children can be born with meconium ileus. Meconium is the material found in the intestines of a newborn baby.
 Later in life patients with CF can suffer from Distal Intestinal Obstructive Syndrome (DIOS)
 Distal intestinal obstructive syndrome (DIOS) – partial or complete intestinal obstruction needs intensive treatment. Lactulose, oral acetylcysteine, Gastrografin®
 Constipation – treat with laxatives
 Other GI problems include: increased gastro-oesophageal reflux, peptic ulcer, rectal prolapse, GI malignancy, intestinal mucosal transport abnormalities, increased motility of small intestine
 Gastro-oesophageal reflux disease. Treatment – PPIs, H2 antagonists, prokinetics

Question 5

Pancreas - how does CF affect

Answer 5

 Exocrine pancreatic insufficiency occurs where the volume of pancreatic secretion is reduced and the secretion is more viscous. This can lead to obstruction of pancreatic ducts and secondary pancreatic damage.
 Prescribe pancreatic enzymes (e.g. Creon®). Adjust dose according to requirements / steatorrhoea. Take with meals and snacks.
 Malabsorption can occur which is exacerbated by pancreatic bicarbonate insufficiency and often is characterised by steatorrhoea. Progressive pancreatic
damage can lead to CF-related diabetes mellitus.
 CF related diabetes mellitus – loss of endocrine function. Treatment, mainly insulin.

Question 6

Liver - how does CF affect

Answer 6

 Liver function can be impaired. Bile ducts become blocked by thick secretions. Bile acids can have a toxic effect on hepatocytes and if left untreated, end stage liver
disease can occur.
 CF related liver disease is related to biliary stasis. Treatment: ursodeoxycholic acid, and, in some cases, vitamin K (Menadiol®). Note, for oral administration of vitamin K the water soluble formulation should be prescribed.

Question 7

Nutrition for CF patients

Answer 7

Patients with CF need increased calorie requirement as:
 Lung disease associated with CF increases energy requirements
 Resting energy expenditure increased
 Patients have malabsorption and fat maldigestion
 Patient may have poor appetite
 Patient may have a chronic chest infection
Patients with CF require nutritional management and they require dietitian reviews.
Patients may need feeds of high calorific value (lipids and carbohydrates). These may be given by oral supplements or may need nasogastric, gastrostomy/jejunostomy feeding.
Fat soluble vitamins may be required: vitamins A, D, E. Vitamin K is not always required. If it is needed, the water soluble form (Menadiol®) should be given. Minerals and trace elements may also be required.

Question 8

CF can affect the reproductive system in the following ways:

Answer 8

 delayed puberty
 infertility problems in the male
 failure of development of vas deferens and epididymis
 infertility problems in the female
 fertility reduced by presence of thickened mucus in the cervix

Question 9

Respiratory System

Answer 9

The lungs are the most affected organs in CF. At birth, the lungs of babies born with CF are structurally normal. Chronic pulmonary infection and inflammation can lead to
bronchiectasis.
Common pathogens involved in respiratory infections include:
 Pseudomonas aeruginosa
 Staphylococcus aureus
 Haemophilus influenzae
 Stenotrophomonas maltophilia
 Burkholderia cepacia
 Non-tuberculous mycobacterium
 Methicillin-resistant Staphylococcus aureus
 Aspergillus fumigatus

The bacterial pathogen can vary with age of patient.

Question 10

Vaccination

Answer 10

Patients should receive vaccination in accordance with the recommended routine childhood vaccination programme. Patients with CF should receive pneumococcal and annual influenza immunisations in accordance with the Department of Health recommendations.

Question 11

Allergies

Answer 11

CF patients often have multiple allergies to antibiotics, which can occur at any time. It is important to have clear and complete documentation of allergies and the nature of the allergy documented in the patient’s notes. If administering antibiotics at home, the CF Trust recommends that the patient has an anaphylaxis kit at home. Patient/parents/carers should be familiar with signs and symptoms of an allergic reaction. Desensitisation regimens can sometimes be used.

Question 12

Prevention and treatment of infection

Answer 12

Patients with CF may need to be treated for an acute infection or may require antibiotics to prevent or control respiratory bacterial infections.

Nebulised antibiotics

Nebulised antibiotics may be needed for patients whose sputum is chronically colonised with Pseudomonas aeruginosa. The following are products licensed for nebulization:
o colistimethate (e.g. Colomycin®, Promixin®). Note that different brands require a different type of nebuliser.
 Side effects: bronchospasm: measure lung function before and after initial dose, monitor for bronchospasm. If bronchospasm occurs and patient does not use a bronchodilator repeat test using a bronchodilator prior to administration of colistimethate.
o tobramycin (Tobi®, Bramitob®)
 Administered on a cyclical basis: 28 day course / 28 day interval 
o aztreonam

Inhaled antibiotics
- A dry powder form of tobramycin used in a hand-held device (Tobi Podhaler®) is administered on a cyclical basis of a 28-day course followed by a 28-day interval. Colistimethate sodium is available as a dry powder for inhalation (Colobreathe®). The counselling advice for this is to rinse mouth with water after each dose

Long-term azithromycin
- The guideline on treatment with antibiotics by the Cystic Fibrosis Trust (2009) advises that a 6-month trial of oral azithromycin should be considered in people with CF who are deteriorating on conventional therapy, irrespective of their infection status. However, not all patients will benefit from this therapy. NICE Evidence Summary 37 considers the evidence to support the off-label use of long-term azithromycin for treating people with CF.
For the purpose of this evidence summary, long-term is defined as 6 months or more, as recommended by the Cystic Fibrosis Trust guideline.

Question 13

Treatment of infection

Answer 13

Longer courses and higher doses of antibiotics are used in patients with CF as they have altered pharmacokinetics. Often, they have increased clearance and volume of distribution and need high plasma concentration of drug to penetrate viscous mucus.
Intravenous antibiotics are used for infective exacerbations and for routine treatment every three months, in those chronically colonised with Pseudomonas aeruginosa. They can be administered in hospital or at home. Some pharmacy manufacturing departments produce ready prepared antibiotic syringes, sodium chloride 0.9% IV flushes and heparin IV flushes.
A sputum culture sample where possible should be taken before starting antibiotic treatment for acute infections. Sputum induction can sometimes be obtained by using
nebulised hypertonic sodium chloride solution.
Antibiotic selection is based on a patient’s clinical symptoms and recent microbiological profile. Patients with chronic infection can develop resistance to antibiotics. Bacteria causing the acute infection can have different sensitivities to those causing the chronic infection. Antibiotic therapy selection will not always correlate with the organism isolated in the microbiology laboratory. It is important to note that this is a specialist area and consultation with senior specialist pharmacists and consultants looking after the patient is always necessary regarding antibiotic therapy selection for patients with CF. Usually at least two antibiotics are used to reduce the risk of antibiotic resistance. A combination of aminoglycoside and a beta-lactam antibiotic has been shown to be synergistic.

Question 14

Intravenous gentamicin, tobramycin and amikacin

Answer 14

These antibiotics have a narrow therapeutic index and require therapeutic drug monitoring.
A patient’s renal function should also be monitored.

Question 15

Infection control

Answer 15

Segregation of cystic fibrosis patients is necessary to avoid patient-to-patient transmission of Pseudomonas aeruginosa and Burkholderia cepacia.
Non-bactericidal effect of antibiotic treatments in cystic fibrosis
Azithromycin is believed to have anti-inflammatory properties and can reduce airway inflammation. It is thought it interferes with the adherence of P.aeruginosa to epithelial cells and the biofilm mode of growth.

Question 16

Mucolytics

Answer 16

Dornase alfa cleaves extra-cellular DNA. It is indicated in the management of cystic fibrosis patients with a forced vital capacity (FVC) of greater than 40% of predicted to improve pulmonary function. It should be used with a jet nebuliser.
Hypertonic sodium chloride solutions can be used immediately before physiotherapy.
Ivacaftor is licensed in cystic fibrosis for the treatment of patients with a G551D mutation in the CFTR gene.
Mannitol improved mucus clearance. It is licensed as an add-on therapy to standard care.
Hyper-responsiveness of the bronchioles must be assessed before starting the therapeutic dose regimen.

Question 17

Allergic bronchopulmonary aspergillosis (ABPA)

Answer 17

ABPA is an allergic response that develops from sensitisation to allergens from a fungus called Aspergillus fumigatus. It colonises the airways of patients with CF (usually adolescents and young adults).

Treatment
Oral corticosteroids: prednisolone (use non-enteric coated or soluble tablets) and itraconazole.

Question 18

Nasal problems

Answer 18

One example is chronic sinusitis.

Treatment: corticosteroids administered nasally

Question 19

Sweat glands

Answer 19

Patients with CF lose more salt in their sweat and supplementation with sodium chloride may be needed in some circumstances e.g. warmer weather when a patient may have increased perspiration.

Question 20

Other considerations - As CF is a chronic disease, the following are things to consider in patients with Cystic Fibrosis

Answer 20

 Bone disease
 Oxygen therapy
 Lung transplantation, Heart/Lung transplantation
 Gene Therapy
 Psychological issues
 Support for patients, siblings, other family members
 Time consuming treatments
 Adherence to medications
 On-going morbidity
 Times of stress
 Clinical psychologist support

Question 21

Neonatal screening for cystic fibrosis

Answer 21

1 Immuno-reactive trypsinogen (IRT) analysis — IRT is significantly raised in babies with CF. Although IRT measurement is highly sensitive, it lacks enough specificity to be a stand-alone test in the diagnosis of
CF. According to the UK screening algorithm, all neonates should undergo this test.

2 DNA analysis for CFTR mutation — if the initial IRT result falls above the 99.5th centile, the DNA is then tested for the four most common mutations that cause CF in the UK. If two mutations are found CF is suspected. If only one mutation is found, another DNA analysis is performed (selected according to the baby’s ethnicity). Statistical
analysis has suggested testing for a greater number of mutations would not significantly reduce the number of false negatives, but it would significantly increase the number of detected carriers; this approach is
therefore not recommended.

3 Sweat test — a sweat test is used to distinguish between true and false positives in “suspected CF” cases. The test involves two pads containing pilocarpine being placed on a small area of skin. The area is stimulated using a small electric current, which releases the pilocarpine and induces sweat production. The sweat is collected and sent for analysis. Infants with positive IRT/DNA screening and sweat chloride >60mmol/L are considered to have a positive CF diagnosis, irrespective
of symptoms. Those with levels <30mmol/L are not considered to have CF unless they also display clinical symptoms. The sweat test is a source for huge parental anxiety and systems need to be in place to minimise the waiting time for results and ensure effective communication between laboratories, specialist centres and families. The earliest the test can be done is the second week of life in newborns weighing 3kg or more

Question 22

Staphylococcus aureus - prophylaxis and acute infection treatment

Answer 22

prophylaxis - Oral flucloxacillin

acute infection - Increased dose of oral flucloxacillin

Question 23

Haemophilus influenzae- prophylaxis and acute infection treatment

Answer 23

prophylaxis - Oral amoxicillin

acute infection treatment - Oral co-amoxiclav or doxycycline

Question 24

Pseudomonas aeruginosa - prophylaxis and acute infection treatment

Answer 24

prophylaxis - Nebulised colistin or tobramycin

acute infection treatment - Oral ciprofloxacin ± nebulised colistin or tobramycin

Question 25

In infants, gastrooesophageal reflux disease (GORD) is usually treated with

Answer 25

a prokinetic drug (eg, domperidone or erythromycin)

combined with an antacid (usually Gaviscon Infant).

Question 26

Distal intestinal obstruction syndrome (DIOS) usually treated with

Answer 26

lactulose or oral acetylcysteine.

• When other treatments have failed, the contrast
  solution Gastrografin can be used orally or rectally to treat DIOS, although it is not licensed for this indication. Fluid intake should be encouraged for three hours following administration of Gastrografin and IV fluid replacement should be considered for neonates

Question 27

Patients with cystic fibrosis and lung disease should be offered a… - what is the first line choice

Answer 27

mucolytic - Dornase alfa • 2.5mg daily (If patient particularly unwell may be increased to twice daily)

If there is an inadequate response, dornase alfa and hypertonic sodium chloride, or hypertonic sodium chloride alone should be considered.

Question 28

Pseudomonas aeruginosa 1st line treatment

Answer 28

eradication therapy with a course of oral antibacterial should be started (by intravenous injection, if they are clinically unwell), in combination with an inhaled antibacterial. An extended course of oral and inhaled antibacterial should follow (consult local protocol).

If eradication therapy is not successful, sustained treatment with an inhaled antibacterial should be offered.

Nebulised colistimethate sodium should be considered as first-line treatment

Question 29

Distal intestinal obstruction syndrome 1st line treatment

Answer 29

Meglumine amidotrizoate with sodium amidotrizoate solution

Question 30

Pulmonary infection

Staphylococcus aureus

Answer 30

Offer flucloxacillin

Question 31

For people with cystic fibrosis and deteriorating lung function or repeated pulmonary exacerbations, offer

Answer 31

long-term treatment with azithromycin

Question 32

for immunomodulatory treatment for cystic fibrosis do not offer

Answer 32

inhaled corticosteroids

Question 33

Pseudomonas aeruginosa

• Infective Exacerbations

Answer 33

Ciprofloxacin 750mg BD
Aztreonam 2g TDS
Ceftazidime 2g TDS
Colistin 2MU TDS
Fosfomycin 4g TDS
Meropenem 2g TDS
Tazocin 4.5g TDS
Tobramycin 10mg/kg OD

Question 34

Aminoglycoside Induced Toxicity

Answer 34

• Two major adverse effects: Ototoxocity, Nephrotoxicity
• Routine monitoring of blood levels
• Once daily tobramycin: Trough level only – within one hour before the second or third dose. Level <1mg/l

Question 35

Nebulised/Inhaled Antipseudomonal Antibiotics

Answer 35

• Reduce the rate of deterioration in patients with chronic
colonisation
• Reduce number of exacerbations
• Maintain lung function
• Examples include:
– Colistin Nebuliser Solution 2MU BD
– Tobramycin Nebuliser Solution 300mg BD alternate months
– Aztreonam Nebuliser Solution 75mg TDS
– Tobramycin Podhaler 112mg BD alternate months

Question 36

Gastrointestinal Disease

Answer 36

• Pancreatic insufficiency – 85%
• Malabsorption of fats and fat soluble vitamins
• Absorption of proteins and carbohydrates affected to a lesser extent
• Exacerbated by pancreatic bicarbonate deficiency

Question 37

Pancreatic/Vitamin Supplements

Answer 37

• Creon 10,000, 25,000 or 40,000

• Vitamin Supplements
Vitamins A and D
Vitamin E Gel Capsule
Paravit
Vitamin K

Question 38

Hyperosmolar Agents

Answer 38

• Facilitates mucus clearance
• Nebulised Sodium Chloride
Can be prescribed in addition to DNase 7% or 3% - usually BD
• Inhaled Mannitol
• 400mg bd
• Not prescribed with DNase

Question 39

CFTR defects

Answer 39

• Class I – CFTR not synthesised
• Class II – Abnormal CFTR synthesised that cannot escape from the endoplasmic reticulum
• Class III – CFTR is synthesised and transported within the cell – disruption in its activation and regulation at the cell membrane
• Class IV – CFTR synthesised and expressed at the cell membrane but chloride conductance reduced
• Class V – CFTR synthesis or processing partly defective
• Class VI – CFTR is synthesised but defective conductance of nonchloride ions

Question 40

Ivacaftor (Kalydeco)

Answer 40

• CFTR potentiator
• Licensed and commissioned to treat patients aged six
years and above who have the G551D mutation (4% of
patients)
• G178R, S549N, S549R, G551S, G1244E, S1251N,
S1255P, G1349D (0.56% of patients)

Question 41

Lumacaftor/Ivacaftor (Orkambi)

Answer 41

• Not recommended for treating cystic fibrosis in people
12 years and older who are homozygous for the F508del
mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
• Lumacaftor is a corrector of the cystic fibrosis transmembrane conductance regulator (CFTR) and ivacaftor is a potentiator of the CFTR