1. Cystic Fibrosis Overview
Unit 1 - Respirology
Cystic Fibrosis
Cystic Fibrosis Overview
CHEO Cystic Fibrosis Team Dr. Tom Kovesi, Pediatric Respirologist, CHEO

2. To understand the genetics of cystic fibrosis
Objectives
To understand the genetics of cystic fibrosis
To understand how abnormalities of CFTR lead to the manifestations of cystic fibrosis
To understand the usual sequence of bacteria colonizing the airways of patients with CF
To understand what bronchiectasis is, how it’s caused, and how it leads to progressive lung damage
Define bronchiectasis, and describe its effects on respiratory function
To recognize non-pulmonary complications of CF
To understand the role of nutritional therapy in CF
To recognize the key elements of therapy of CF
To understand the impact of CF on the patient and his or her family
Unit 1 (Respirology) – CF Overview – Dr. Tom Kovesi

3. 1:20 Caucasians is a carrier; incidence in Canada about 1:3500
The Genetics
Autosomal recessive
Defect in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a chloride channel, encoded on 7q
> 1500 known CFTR mutations; commonest is deltaF508 (found in ~70% of CF patients, 90% of Caucasian patients; about 50% of CF patients are deltaF508 homozygous
1:20 Caucasians is a carrier; incidence in Canada about 1:3500
Incidence decreasing: ? Result of genetic counselling
CF Newborn screening now available in several provinces

4. Lumen Cell Interior CFTR
CFTR normally transports Cl- out of the cell. Na+ and water follow passively, helping liquefy mucous lining hollow tissues (e.g. airway)
CFTR failure reduces Cl- secretion & enhances Na+ resorption, reducing water content of intraluminal mucous
Lumen
H20
Na+ Cl-
Mucous
Transmembrane
Domain 1
Transmembrane
Domain 2
Pore
Cl-
Cl-
Na+
Na+
Nucleotide
Binding Domain 1
Nucleotide
Binding Domain 2
Cell Interior
R-domain

5. This disrupts organ function
CF: A Sticky Situation
Excessively-thick mucous obstructs all hollow organs which contain mucous:
bronchial tubes,
nasal passages,
biliary tree,
pancreas,
vas deferens
This disrupts organ function
In the respiratory tract, prolonged retention of mucous leads to bacterial superinfection

6. Cell Bacterial binding
Mutant CFTR has an abnormal glycolipid side chain
Which is abnormally sticky for Staphylococcus aureus and Pseudomonas aeruginosa
Early airway binding & infection by Staphylococcus aureus and Hemophilus influenzae, causing increasing airway damage, is then followed by infection by chronic infection with Pseudomonas aeruginosa
Cell

7. The Slime Factor
Chronic airway damage from infection leads to subepithelial scarring
Scarring reduces glucose diffusion from mucosa into airway
In presence of high O2, low glucose environment, P. aeruginosa colonies produces slime, which shield the microcolonies from immune attack
Pseudomonas colony

8. Infection and Inflammation
Pseudomonas produces elastase, which destroys elastin network maintaining bronchial rigidity (1)
Elastase also cleaves anti-pseudomonal IgG (2)
Slime (3) (& lack of opsonins) reduces neutrophil effectiveness
Neutrophils also release elastase, causing further airway damage (4)
In presence of thick mucous and neutrophil elastase, Pseudomonas loses it’s motility, forming aggregates that resist clearance & antibiotics (5) 2 4
Staudinger, Am J Respir Crit Care Medicine 2014; 189:
Zemanick, Am J Respir Crit Care Medicine 2014; 189:763-5. 1 3 5

9. Bronchiectasis
Destruction of elastin network which maintains bronchial wall rigidity causes bronchial walls to become soft, dilated, and baggy, or
Soft airway walls collapse during cough, promoting secretion retention, and baggy pockets promote more mucous accumulation
Bronchiectasis
Normal
Viscous cycle of progressive accumulation of infected mucous & inflammation.
Distal alveoli may fibrose from infection, or following obstruction by mucous and atelectasis

10. Chronic Lung Infection in CF
Most patients are infected with:
Staph aureus in 1st year of life,
Hemophilus influenzae by 2 years,
Pseudomonas aeruginosa by 5-7 years;
Nosocomial infection with Burkholderia cepacia can occur, generally in adolescence
Chronic infection leads to chronic cough, wheeze, sputum production, and dyspnea
Viral infections (increased mucous, reduced immune function), promotes bacterial proliferation & increased inflammatory response, with transient increase in symptoms

11. Pancreatic Disease & Malnutrition
Obstruction of pancreatic ducts leads to pancreatic enzymes destroying the pancreas, leading to pancreatic insufficiency in most patients
About 15% of CF patients have 1 or more “mild” CFTR mutations, associated with preserved pancreatic function and somewhat milder lung disease
Absence of pancreatic enzymes in intestines leads to malabsorption of fat, protein, leading to:
malnutrition, wasting, and stunted growth
abdominal pain and cramping
chronic diarrhea with oily, foul, frequent stools
rectal prolapse
Symptoms of fat-soluble vitamin deficiency (A, D, E and K)
Malnutrition impaires immune function, allowing enhanced bacterial growth & more rapid progression of lung disease

12. Bowel Obstruction
Inspissated mucous generally eliminates exocrine pancreatic function by time of birth
Thick meconium may lead to Meconium ileus and bowel obstruction in neonates
Unabsorbed food residues may lead to partial small bowel obstruction called Distal Intestinal Obstruction Syndrome (or Meconium Ileus Equivalent) in children & adults

13. Other Affected Organs
Thick mucous obstructs nose & sinuses, leading to nasal discharge, chronic sinusitis, and nasal polyps
Thick biliary secretions cause bile retention in liver, damaging adjacent hepatocytes and leading to focal biliary cirrhosis
Destruction of pancreatic islet cells leads to Type 1 Diabetes mellitus
Thick secretions cause obstructive azospermia in males and reduced fertility (thick cervical secretions) in females
Chronic hypoxia from severe lung disease may lead to pulmonary hypertension and cor pulmonale

14. Sweat Chloride Genetic Testing Newborn screening
Diagnosis
Sweat Chloride
In sweat ducts, Na+ and Cl- are secreted into the ducts.
CFTR is inserted backwards, to draw Na+ and Cl- out of the sweat ducts, to minimize their loss during perspiration
An elevated sweat chloride is main test used to diagnose CF
Genetic Testing
Most panels screen for ~70 of 1500 known CFTR mutations
CFTR gene sequencing can be performed in unclear cases
Newborn screening
Several provinces screen heel prick blood for trypsinogen (pancreatic enzyme that leaks out of pancreas when ducts are blocked.
Diagnosis then confirmed using CFTR screening and/or sweat chloride

15. Patients followed in multidisciplinary clinic:
Monitoring
Patients followed in multidisciplinary clinic:
physicians,
nurses,
dieticians,
physiotherapists,
social workers,
respiratory therapists
pharmacists
Patients seen every 3 months (& as needed); check:
Nutritional status,
sputum cultures,
PFT (child 6 yrs & older) every visit
Look for obstructive changes
Annual:
blood work
chest X-ray

16. Chest X-ray
Chest X-ray of a CF patient showing classic changes of bronchiectasis, including tram tracks (look at the left upper lobe and right lower lobe) and dilated, end-on bronchi (distal left upper lobe)
Unit 1 – CF Overview – Dr. T. Kovesi

17. Chest Assisted Airway Clearance (“chest physiotherapy”) Antibiotics
CF Therapy
Nutritional Support
Chest Assisted Airway Clearance (“chest physiotherapy”)
Antibiotics
Other Pulmonary Therapies

18. Treatment: Nutritional Rehabilitation (1)
High-fat, high calorie diet given to prevent malnutrition, replace excess fecal losses from malabsorption, and support increased energy requirements caused by chronic infection and increased work of breathing
Pancreatic enzyme supplements (contain lipase, protease, amylase) given with each meal
Fat-soluble vitamin supplementation
Ursodeoxycholic Acid improves bile flow in children with CF-associated liver disease
Insulin is used in patients with CF-associated diabetes

19. Treatment: Nutritional Rehabilitation (2)
In summer, increased dietary sodium to compensate for excess losses in sweat, to prevent hypochloremic dehydration
If severe malnutrition, supplemental feeds:
Most often, by Gastrostomy tube
Caloric support essential for growth and to optimize immune status, reducing rate of airway bacterial proliferation and decline in lung function

20. Chest Assisted Airway Clearance Techniques (@Chest Physiotherapy@)
Essential to promote removal of infection secretions from the airways by coughing
Many techniques available:
Mechanical percussion (“clapping”)
Positive Expiratory Pressure Technique
Electronic vibrating chest Vest, etc.
Many patients find physio tedious, and compliance is challenging

21. Antibiotics
Antibiotics need to cover organisms patient is known to be colonized with
Oral antibiotics given for mild pulmonary exacerbations
Intravenous antibiotics given for more severe exacerbations in hospital, combined with intensive physiotherapy and nutrition
Inhaled antibiotics (tobramycin) may be given for long-term suppression of Pseudomonas in the airways

22. Treatment: Lung Disease (2) Additional Therapies
Anti-inflammatories: decrease airway inflammation
Long-term azithromycin has anti-inflammatory effects
Mucolytics: reduce sputum viscosity
Inhaled DNase (dornase-alpha) lyses DNA released by degenerating neutrophils, which can further reduce sputum viscosity
Inhaled hypertonic saline draws water into mucous, thinning mucous
CFTR modulators: ivacaftor activates chloride channel in patients with G551D (& a couple very rare) CFTR mutations

23. Treatment: Lung Disease (3) Additional Therapies
Bronchodilators:
Airway inflammation may lead to airway hyperreactivity & bronchospasm
Asthma therapy:
Used in some patients with airway hyperreactivity
Oxygen therapy for advanced lung disease

24. Treatment – In Summary
What are the things we do most likely to improve prognosis and survival in CF patients?
High calorie diet (and pancreatic replacement enzymes to absorb those calories)
Assisted Airway Clearance (chest physiotherapy)
Antibiotics
For exacerbations (PO or IV)
Maintenance, such as inhaled tobramycin for chronic Pseudomonas infection (or to eradicate newly-acquired Pseudomonas)
Mucolytics:
Dornase-alpa
CFTR Gene modulators:
Ivacaftor – CFTR chloride channel potentiator for specific genotypes (G551D)

25. Prognosis
Median survival in Canada is in 40’s
Best predictor of outcome at present is FEV1: FEV1 of < 30% predicted is associated with a 50% 2-year survival
Lung Transplantation becomes an option when FEV1 is < 30% predicted, as 2-year survival after lung transplantation is 60%
Complications after lung transplantation include sepsis (multi-resistant organisms), chronic rejection (bronchiolitis obliterans)

26. Effects at multiple levels
Psychosocial Impact
Effects at multiple levels
High levels of stress and anxiety – patient & family
Demanding treatment regimen
1 hour/day or more
Effects on family - siblings
Academic, career choices
Effects on relationships
Treatment Adherence
Effects of depression
Family functioning
Education level
Motivation
Organization
Family planning for parents: future children

27. Sometimes it’s in the genes…
And sometimes it’s in the expression!