Cystic fibrosis Flashcards
What is the inheritance pattern of cystic fibrosis?
Autosomal recessive
What is the carrier rate and incidence rate of cystic fibrosis?
Carrier rate: 1 in 25
Incidence rate: 1 in 2500 live births
What is the trend in life-expectancy in CF?
have increased from just a few years to the mid-30s, expected to be into 40s for current newborns
What is the cause of CF in terms of genetics?
defective protein called CF transmembrane conductance regulator (CFTR)
this is a cyclic AMP-dependent chloride channel found in the membrane of cells; gene for CFTR located on chromosome 7
over 900 gene mutations discovered that cause distinct defects in CFTR but most frequent in UK is ΔF508
What proportion of cases of CF in the UK are caused by the ΔF508 mutation?
78%
On which chromosome is the gene for CFTR located?
chromosome 7
What are the effects of the 6 classes of mutation in the CFTR protein? What is the trend as you go down the classes?
- nonsense/frameshift mutation, no protein synthesised
- Incorrect folding: cannot traffic to membrane
- Channel opening defect
- Pore abnormalities cause decreased conductance
- Splicing abnormality - reduced protein synthesis
- Shortened half-life of protein
Trend = more CFTR-mediated chloride transport with higher class
What class of CFTR mutation is caused by ΔF508?
Class II: incorrect folding, cannot traffic channel to membrane
What are 3 benefits of identifying the gene mutation involved in CF within a family?
- Prenatal diagnosis
- Carrier detection in wider family
- Precise genotype now can help guide treatment - CFTR potentiators (Ivacaftor) and CFTR correctors (Lumicaftor)
What are 2 types of drugs that work based on the precise genotype of CF and how do they work?
- CFTR potentiators e.g. Ivacaftor: restore function of CFTR in class III and IV mutations
- CFTR correctors e.g. Lumicaftor: partially restore CFTR number in class II defects
What is an example of a CFTR potentiator?
Ivacaftor
What is an example of a CFTR corrector drug?
Lumicaftor
What causes the multisystem features of CF in terms of pathophysiology?
results from abnormal ion transport across epithelial cells
How does CF cause airway effects?
- In airways, abnormal ion transport across epithelial cells leads to reduction in airway surface liquid layer, and consequent impaired ciliary function and retention of mucopurulent secretions
- chronic endobronchial infection with specific organisms e.g. Pseudomonas aeruginosa ensues
- Dysregulated inflammation and defence against infection
What are 4 key examples of organisms which cause chronic endobronchial infection in CF?
- Staphylococcus aureus (initially)
- Haemophilus influenzae (initially)
- Pseudomonas aeruginosa
- Burkholderia species
What effect can CF have on intestinal function in infants?
thick viscid meconium is produced leading to meconium ileus in 10-20% of infants
How does cystic fibrosis affect pancreatic function?
pancreatic ducts become blocked by thick secretions, leading to pancreatic enzyme deficiency and malabsorption
How does CF affect the sweat?
abnormal function of sweat glands leads to excessive concentrations of sodium and chloride in the sweat
How is CF generally diagnosed?
all newborn infants born in UK are screened
How does CF screening take place in the newborn?
immunoreactive trypsinogen (IRT) is raised in newborn infants with CF, measured in routine heel-prick blood taken for biochemical screening
if samples contain raised immunoreactive trypsinogen, screened for common CF gene mutations, and infants with two mutations have a sweat test to confirm the diagnosis
What are 3 features that some children with CF who are missed by screening may present with?
- Recurrent chest infections
- Faltering growth
- Malabsorption
What is the result of chronic chest infection in CF?
damage of bronchial wall, bronchiectasis, abscess formation
What are 6 respiratory features of cystic fibrosis with chronic infection on respiratory examination?
- Persistent ‘wet’ cough, productive of purulent sputum
- Hyperinflation of chest due to air trapping
- Coarse inspiratory crepitations
- Expiratory wheeze
- Finger clubbing (if established disease)
What is the biggest killer in CF and what proportion does it affect?
Respiratory failure - 95%
What is the key feature of CF in the newborn and what proportion of babies with CF does it affect?
Meconium ileus - 10-20%
What causes meconium ileus in the newborn and what are 3 symptoms?
inspissated meconium causes intestinal obstruction
- Vomiting
- Abdominal distension
- Failure to pass meconium in the first few days of life
What are 2 options for management of meconium ileus in the newborn?
- Surgery usually required
- Gastrografin enema may relieve obstruction
What is the essential diagnostic procedure for CF and what does it involve?
- Sweat test - to confirm concentration of chloride in sweat is markedly elevted (Cl 60-125mmol/L in CF, normal is 10-40mmol/L)
- Sweating stimulated by applying low-voltage current to pilocarpine applied to the skin
- Sweat collected from special capillary tube or absorbed onto weighed piece of filter paper
What is the normal range for chloride ions in sweat and what is it likely to be in CF?
- normal: 10-40mmol/L
- CF: 60-125mmol/L
What causes frequent diagnostic errors from the sweat test?
if inadequate volume of sweat collected
How can a confirmation of a diagnosis of CF be made following the sweat test?
testing for gene abnormalities in the CFTR protein
What type of approach is needed to manage CF?
multidisciplinary approach
How often should patients with CF be reviewed and where?
at least annually in specialist centre
What is the aim of therapy in CF?
prevent progression of lung disease and maintain adequate nutrition and growth
What are 8 potential complications of CF to monitor for at reviews?
- Nasal polyps, sinusitis
- Allergic bronchopulmonary aspergillosis (ABPA)
- Diabetes mellitus (often insulin-dependent)
- Cirrhosis and portal hypertension
- Distal intestinal obstruction syndrome (DIOS, meconium ileus equivalent)
- Pneumothorax or recurrent haemoptysis
- Concern about sterility in males
- Rectal prolapse
What are 7 things to assess for in terms of respiratory examination at the CF review?
- Hyperexpansion due to air trapping
- Harrison’s sulcus
- Coarse inspiratory crepitations and/or expiratory wheeze
- Chest infection
- Clubbing
- Scar from operation for meconium ileus as neonate?
- Central venous line e.g. Portacath for IV abx to aggressively treat infection
What is a concern regarding salty sweat to ask patients about at their review?
may lead to dehydration in hot weather
What are 4 things to consider regarding nutrition and growth at the CF review?
- aiming for normal growth
- gastrostomy is option for overnight feeding for extra calories
- ensure taking sufficient pancreatic replacement therapy
- ensure taking fat soluble vitamins
What are 7 aspects of management of chest problems in CF to review?
- Spirometry - to identify deterioration
- Regular breathing exercises?
- Physiotherapy and exercise?
- Bronchodilator therapy - is it optimal?
- Chest infection - acute or chronic and its treatment?
- Nebulised antipseudomonal antibiotics and DNase?
- Avoidance of direct contact with other affected patients other than family members?
What are 3 things to consider as part of a general overview at a CF review appointment?
- School attendance and performance
- Specific problems with managing their disease
- Psychological needs
Overall, what are 8 parts of the review appointment for CF to remember?
- Chest examination
- Monitor for potential complications
- Sputum - acute or chronic colonisation?
- Nutrition + growth
- Review of chest problems
- General overview
- Dehydration due to salty sweat
- Siblings affected?
What is the major respiratory problem in CF?
recurrent and persistent bacterial chest infection
What are 2 ways that respiratory monitoring is performed in children and what does this depend on?
- Older children: lung function measured regularly by spirometry
- Younger children: symptoms
How is spirometry used to determine lung function in older children with CF?
FEV1 expressed as a percentage of predicted for age, sex and height is indicator of clinical severity, and declines with disease progression
What role does physiotherapy for respiratory management of CF and when is this introduced?
- introduced from diagnosis, should have physiotherapy at least twice a day.
- in younger children, parents taught to perform airway clearance at home using chest percussion and postural drainage
- older patients perform controlled deep breathing exercises and use variety of physiotherapy devices for airway clearance
- physical exercise beneficial and encouraged
What treatment for recurrent and persistent chest infections is available for CF?
- many specialists recommend continuous prophylactic oral antbiotics, usually flucloxacillin, with additional rescue oral antibiotics for increases in respiratory symptoms or decline in lung function
- persisting symptoms or signs require prompt and vigorous IV therapy to limit lung damage, usually 14 days via PIC (peripherally inserted central) line
What is the treatment for persisting new symptoms or signs of chest infection in CF that aren’t cleared with rescue oral antibiotics?
Prompt and vigorous IV therapy, usually for 14 days via PIC (peripherally inserted central) line
Parents increasingly taught to administer IV abx at home to decrease school/acitivity disruption
Which type of infection is associated with a more rapid decline in lung function in cystic fibrosis?
Pseudomonas auruginosa
How can the rapid decline in lung function due to Pseudomonas infection be slowed?
daily nebulised antipseudomonal antibiotics
What are 2 therapies available to decrease viscosity of sputum and increase its clearance in CF?
- Nebulised DNase
- Hypertonic saline
What are 2 treatments that can be given in CF to reduce respiratory exacerbations?
- Regular nebulised hypertonic saline
- Macrolide antibiotic azithromycin
What can be done for more severe CF requiring regular IV abx when venous access becomes troublesome?
Implantation of central venous catheter with subcutaneous acess port e.g. Portacath - simplified access
What are the issues with inserting a central venous catheter e..g Portacath for regular IV abx therapy in CF?
require monthly flushing, complications may develop
What is the only therapeutic option for end-stage CF lung disease?
bilateral sequential lung transplantation
What is the current survival rate following bilteral lung transplant for CF?
50% survival at 10 years - continues to increase
What proportion of children with CF have pancreatic exocrine insufficiency?
over 90%
What are the 3 types of enzymes that are deficient in pancreatic exocrine insufficiency?
lipase
amylase
proteases
What does pancreatic enzyme insufficiency result in?
maldigestion and malabsorption - this leads to faltering growth if untreated, with frequent large, pale and greasy stools (steatorrhoea)
How can pancreatic insufficiency be diagnosed in CF?
demonstrated low faecal elastase
What are 4 aspects of nutritional management in CF?
- Dietary status should be assessed regularly
- Pancreatic insufficiency treated with oral enteric-coated pancreatic replacement therapy - take with all meals and snacks
- High calorie diet essential - 150% dietary intake, overnight gastrostomy
- Fat-soluble vitamin supplements
Why do CF patients require supplementation of fat-soluble vitamins?
difficuly absorbing fats due to pancreatic enzyme insufficiency - leads to malabsorption of fat-soluble vitamins
What determines dosage of oral pancreatic replacement therapy?
taken with all meals and snacks
dosage adjusted according to clinical response
What are 2 ways that a high-calorie diet can be achieved in CF?
- Dietary intake recommended at 150% of normal
- Overnight feeding via gastrostomy increasingly used
What is the most common complication of CF as patients grow into adult life?
diabetes mellitus - due to decreased pancreatic endocrine function
What proportion of CF patients have evidence of liver disease, and what possible clinical presentations of this?
up to a third
- Hepatomegaly on palpation
- Abnormal liver function on blood tests
- Abnormal ultrasound
How can early liver disease in CF be managed?
regular ursodeoxyholic acid to improve flow of bile may be beneficial
What can liver disease progress to in CF in rare instances and how is this managed?
Cirrhosis, portal hypertension, and ultimately liver failure
Liver transplant very successful
What is distal intestinal obstruction syndrome (DIOS)?
meconium ileus equivalent: viscid mucofaeculent material obstructs the bowel
How can distal intestinal obstruction syndrome be treated?
usually cleared by combination of oral laxative agents
What are 2 late respiratory complications of CF?
- Pneumothorax
- Life-threatening haemoptysis
What is one behavioural measure to reduce incidence of chest infections in CF and why?
segregated CF patients, advised not to socialise with other people with CF - as increasing concern over transmission of virulent strains of Pseudomonas and Burkholderia cepacia
How is fertility affected in females?
usually normal, unless severe lung disease can tolerate pregnancy well
How is fertility affected in males in CF?
virtually always infertile due to absence of vas deferens, but can father chidlren through intracytoplasmic sperm injection
What psychological support is provided in CF?
psychological and emotional support provided to children and families as chronic and ultimately fatal illness; adolescents have particular needs which must receive special consideration
older adolescents should transfer to specialist adult CF care
What hopes for the future treatment of CF are there, and what is the current limitation?
CFTR potentiators and CFTR correctors may significantly improve outcomes
Availability limited by high cost
What are 4 features of CF in infancy?
- Prolonged neonatal jaundice
- Growth faltering
- Recurrent chest infections
- Malabsorption, steatorrhoea
What are 4 features of CF in the young child?
- Bronchiectasis
- Rectal prolapse
- Nasal polyp
- Sinusitis
What are 6 possible features of CF in the older child and adolescent?
- Allergic bronchopulmonary aspergillosis (ABPA)
- Diabetes mellitus
- Cirrhosis and portal hypertension
- Distal intestinal obstruction syndrome (DIOS)
- Pneumothorax or recurrent haemoptysis
- Sterility in males
