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

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

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

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

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

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

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

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; 189:812-24. Zemanick, Am J Respir Crit Care Medicine 2014; 189:763-5. 1 3 5

Bronchiectasis Destruction of elastin network which maintains bronchial wall rigidity causes bronchial walls to become soft, dilated, and baggy, or Abronchiectasis@ 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

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 (@Pulmonary Exacerbation@)

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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)

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

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