Nuts and Bolts: Pulmonary Overview Starla G. Martinez, M. D Nuts and Bolts: Pulmonary Overview Starla G. Martinez, M.D. Akron Children’s Hospital Akron, Ohio November 1, 2017

Starla G. Martinez, M.D. I have no relationships to disclose. Presenter Disclosure Starla G. Martinez, M.D. I have no relationships to disclose.

Overview What is CF? What causes it? Who does it affect? How is the diagnosis made? What are the symptoms of CF? What is the primary problem in CF? What are the treatments for CF? What are the benefits of treatment?

What is Cystic Fibrosis? Most common life-shortening genetic disorder for Caucasians Autosomal recessive Roughly 35,000 affected persons in the U.S. 900+ new patients diagnosed per year in the U.S. 60% of these are now detected by newborn screening 80,000 - 120,000 affected persons worldwide

What is CF?: Key Points to Know Multi-system, multi-faceted disorder Lung disease Major problem in CF Destructive inflammation-infection cycle Lifelong therapy is required for best outcome

What Causes CF? A defect (mutation) in a gene on chromosome 7 that encodes a protein called CFTR CFTR: Anion channel that regulates secretion of chloride, bicarbonate, fluid Found in epithelial cells in multiple tissues Also found in other cells, e.g. neurons

www.acf.org www.healthopedia.com

www.udel.edu

Normal CFTR AIRWAY Cl- Na+ water INSIDE CELL

Defective (or absent) CFTR Thick Dehydrated Secretions AIRWAY Na+ water Cl- INSIDE CELL

Genetics of CF in the US 2000+ mutations Not all cause CF CF-causing mutations are divided into 5 classes, based on function of CFTR

Classification of CFTR mutations CF Registry, 2015

Relative frequency of mutations 25 mutations cause 90% of the cases in Caucasian population At least one copy of F508del is found in 86% of Caucasians with CF G542X and G551D are the next most common at 4-5%

Who is affected? Epidemiology of CF in U.S. Caucasian 1:2,500-3,500 live births Hispanic 1:4,000-10,000 live births African-American 1:17,000 live births Asian-American 1:30,000 live births

1986-2015 CF population in US CF Registry, 2015

# of new CF diagnoses, 1991-2015 CF Registry, 2015

Current Diagnosis of CF (2017 Guidelines) Universal newborn screening in US since 2010 About 2/3 of new CF cases are now in asymptomatic infants Combination of testing is recommended, based on findings of tests Sweat chloride Genotyping CFTR function testing Ref. # 13

Ref. # 13

How is diagnosis made? Clinical presentation of CF (+NBS, signs/symptoms, family history), then: Sweat Test ≥ 60 mmol/L 30-39 mmol/L <29 mmol/L CFTR Genetic Analysis No mutations Undefined or unknown significance 2 CF-causing mutations CFTR Physiologic testing Normal Equivocal CFTR dysfunction CF unlikely CF Not resolved Diagnosis

Newborns with positive screening but inconclusive testing CRMS: CFTR-Related Metabolic Syndrome OR CFSPID: Screen-Positive, Inconclusive Diagnosis

Non-screened individuals with inconclusive diagnosis CFTR-related disorder Identified CFTR-related issue but without meeting criteria for diagnosis of CF Avoid the terms “atypical CF” or “non-classic CF”

CF vs. other diagnoses, 2015 CF Registry, 2015

Key points about diagnosis of CF Sweat chloride test is still recommended Normal sweat chloride is < 30 mmol/L for all ages CFTR2 is an on-line resource for obtaining info about specific mutations www.cftr2.org

CF: Many systems are affected Abnormal epithelial cell function leads to problems in multiple systems: Lungs Sweat glands Vas deferens GI tract Liver Pancreas Bones CFTR Sweat glands Lungs Reprod. tract GI tract Liver Pancreas Bones

What are the symptoms at diagnosis? 1995 2015 Respiratory symptoms 51% 18% Failure-to-thrive 43% 7% Steatorrhea 35% 5% Meconium ileus 19% 10% Family history 17% 12% * Symptoms may be simultaneous Ref. #14 and CF Registry, 2015

What is the primary problem in CF? Pulmonary disease is the major cause of morbidity and mortality Primary cause of death Percent of deaths Respiratory failure 65% Complication of lung transplant 19% Liver disease 3% Other or unknown 13% CF Registry, 2015

Pulmonary Disease: Vicious Cycle Defective CFTR Abnormal Airway Surface Environment Airway Damage Infection and Inflammation Bronchial Obstruction

Inflammation out of control Neutrophilic inflammation Inflammation persists, even when infection is at a low level Result of chronic inflammation is airway damage Talk about how neutrophils are WBCs that come from the blood to fight infection. In healthy, non-CF lungs, there is a certain amount of baseline presence of neutrophils to keep things under control (to fight off usual invaders). If I get pneumonia, I get a big increase in the infection-fighting cells to fight the pneumonia, but then they gradually go back to baseline (normal waterfall). The problem in CF is that the waterfall never goes back to normal; it may lessen, but there’s always more inflammation than there should be. And it’s this inflammation, and everything that goes with it, that damages the airway over time.

Pulmonary Problems - 1 - Chronic airway infection and inflammation - Chronic cough and sputum production - Typical airway infections - Staphylococcus aureus: “Staph” - Haemophilus influenza: “H. flu” - Pseudomonas aeruginosa - Burkholderia cepacia

CF Registry, 2015

www.healthopedia.com

Inflammation and mucus plugging Ref. # 16 and www.udel.edu

Pulmonary Problems - 2 - Inflammation and infection lead to airway damage: - Mucus plugging and bronchiectasis - Pneumothorax (<1% incidence per year) - Massive hemoptysis (<1% incidence per year)

Pulmonary Problems - 3 Other respiratory tract complications: - Nasal polyps - Pansinusitis Normal Abnormal

Pulmonary Function in CF “PFTs” or “spirometry” FEV-1 % predicted Ages 4-6 years and up Image from breathe.ersjournals.com

Normal PFT

Moderate obstruction

Severe obstruction

Progression of lung disease: PFTs 100 After treatment 80 Exacerbations 60 FEV1 (% predicted) 40 20 Overall survival most closely correlates with FEV1 Age in years

Pulmonary effect of CF over time: Gradual decline in lung function What happens if we don’t treat CF?

A fatal disease without therapy 35 30 Median age of survival 25 20 Age (years) 15 10 5 1930 1940 1950 1960 1970 1980 1990 2000 2010 Year 0.5 years in 1940

At least 3 pillars of treatment… What is the treatment program for CF? Images Copyrighted by Historylink101.com & found at Greek Picture Gallery At least 3 pillars of treatment…

What is the treatment program for CF? Manage airway obstruction Appropriate nutrition for ample energy to fight infection and inflammation Antibiotics to combat lung infection Treatment is aimed at preventing PFT decline

Clinical Practice Guidelines at cff.org/care Age-specific: Diagnosis; Infant, Pre-school, Adult System-specific: Diagnosis; Nutrition and GI Specific infections Respiratory (chronic medications, airway clearance, exacerbations, pneumothorax and hemoptysis) Condition-specific: E.g. CF-related diabetes, bone disease, liver disease, vitamin D Other: e.g. depression and anxiety

Outcome with 3 pillars of CF treatment 35 30 25 20 Age (yrs) 15 10 5 1930 1940 1950 1960 1970 1980 1990 2000 2010 Year 0.5 years in 1940 0.5 yrs in 1940, 2 yrs in 1950 Ref. # 7

1st Pillar: Manage airway obstruction Bronchodilators Airway clearance Hypertonic saline Dornase alfa (DNase)

Flutter ® : Video Video courtesy of Michael W. Konstan, MD

the one that will be used! Airway Clearance: General Concepts Daily adherence Proper technique Adequate frequency Adequate duration of therapy The best therapy is… the one that will be used!

1st Pillar: Manage airway obstruction Bronchodilators Airway clearance Hypertonic saline Dornase alfa (DNase)

Hypertonic Saline 7% Increases airway surface liquid Improves defective mucociliary clearance In patients ≥ 6 years: Modest improvement in FEV1 but no effect on rate of decline Significant decrease in pulmonary exacerbations In patients < 6 years, no clear decrease in pulmonary exacerbations Remember that the Atlantic Ocean is about 3.5% salinity Ref. # 18 & 19

Dornase alfa Large amount of DNA in CF sputum DNA released from neutrophils DNA contributes to the thick sticky mucus in CF Dornase alfa breaks down DNA & helps reduce the viscosity of mucus in the CF airway Several studies show: Improvement in FEV1 Slower rate of decline in FEV1 Ref. # 16 & 17

2nd pillar: Appropriate nutrition More in later session today

3rd pillar: Antibiotics Manage airway obstruction Appropriate nutrition Antibiotics

Antibiotics in CF Eradication (?) of initial infections Acute exacerbation Antibiotics based on culture results Oral, inhaled, intravenous Home vs. hospital treatment Prophylaxis Inhaled antibiotics Oral antibiotics? Immunomodulators, e.g. azithromycin The question mark is because we don’t know if we’re actually getting rid of the infection or just getting it to an undetectable level.

Treatment of pulmonary exacerbations IV Antibiotics Increased airway clearance Aggressive nutrition Monitor for toxicity Treat / screen for complicating diagnoses ABPA, CFRD, atypical mycobacteria Discontinue therapy based on response (PFT, exam)

Anti-inflammatory therapy 4th pillar: Anti-inflammatory therapy 4 Airway clearance Aggressive nutrition Antibiotics Anti-inflammatory therapy

Chronic airway inflammation in CF Exaggerated neutrophilic inflammatory response Contributes to lung damage Ameliorate lung damage & loss of pulmonary function with anti-inflammatory therapy Proof of concept: prednisone Example of “high-dose” ibuprofen

Anti-Inflammatory: High Dose Ibuprofen Primary outcome measure: annual rate of change in FEV1 20 40 60 80 100 Age in years FEV1 (% predicted) Ibuprofen Placebo Treatment group had less rapid decline in FEV1: The slope of the line had changed!

Candidates for anti-inflammation Recommended? Azithromycin YES Dornase alfa YES Ibuprofen YES Inhaled corticosteroids NO Anti-oxidant: N-acetylcysteine Not enough info Leukotriene modifiers Not enough info Inhaled anticholinergics Not enough info Ref. # 29

Gene-based and CFTR modulators 5th pillar: 5 Gene-based and CFTR modulators Ivacaftor (initial FDA approval 2012) Improves function of CFTR chloride channel Alone, works best for G551D mutation FDA-approved for certain mutations in patients 2+ years Lumacaftor-Ivacaftor (initial FDA approval 2015) Combo helps get CFTR to cell surface (lumacaftor) and then function better (ivacaftor) FDA-approved for homozygous F508del patients ages 6+ years

Is our multi-pillared approach working? Airway clearance Aggressive nutrition Antibiotics Anti-inflammatory therapy Gene-based and CFTR modulators

Improvement in median FEV1 since 1986 CF Registry, 2015

1986-2015 Median Predicted Survival (5-year increments) 44 40 36 Age in Years 32 28 CF Registry, 2015

Median Predicted Survival in CF 1940-2015 41.7 years Is it working? Yes!

Where should we focus our efforts? Chronic Medications Median % eligible for whom this was prescribed (2010  2015) Dornase alfa 78  90 Inhaled tobramycin 70  71 Azithromycin 70  68 Hypertonic saline 50  70 Ibuprofen 4  <1 Inhaled aztreonam 36  41 CF Registry, 2015

% of eligible patients prescribed recommended chronic medications CF Registry, 2015

Parting Thoughts CF is not yet fully curable, but life-extending therapies are available and effective Let’s do WELL what we know to be beneficial Our efforts should be directed at: Maintaining “many-pillared” treatment Seeking new therapies Optimizing use of current therapies so our patients are healthy enough to benefit from future therapies!

Thank you!

References – See Handout

Mucus plugging Normal

Normal Bronchiectasis Radiopaedia.org

Normal lung Bronchiectasis http://mediswww.meds.cwru.edu/ecsample http://www.pathguy.com/lectures/cystic_fibrosis.jpg