1. 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

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

3. 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?

4. 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 affected persons worldwide

5. 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

6. 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

9. Normal CFTR
AIRWAY
Cl-
Na+
water
INSIDE CELL

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

11. 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

12. Classification of CFTR mutations
CF Registry, 2015

13. 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%

14. 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

15. CF population in US
CF Registry, 2015

16. # of new CF diagnoses,
CF Registry, 2015

17. 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

18. Ref. # 13

19. 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

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

21. 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”

22. CF vs. other diagnoses, 2015
CF Registry, 2015

23. 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

24. 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

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

26. 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

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

28. 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.

29. 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

30. CF Registry, 2015

32. Inflammation and mucus plugging
Ref. # 16 and

33. 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)

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

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

36. Normal PFT

37. Moderate obstruction

38. Severe obstruction

39. 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

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

41. A fatal disease without therapy35 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

42. 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…

43. 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

44. 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

45. Outcome with 3 pillars of CF treatment35 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

46. 1st Pillar: Manage airway obstruction
Bronchodilators
Airway clearance
Hypertonic saline
Dornase alfa (DNase)

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

48. 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!

49. 1st Pillar: Manage airway obstruction
Bronchodilators
Airway clearance
Hypertonic saline
Dornase alfa (DNase)

50. 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

51. 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

52. 2nd pillar: Appropriate nutrition
More in later session today

53. 3rd pillar: Antibiotics
Manage airway obstruction
Appropriate nutrition
Antibiotics

54. 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.

55. 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)

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

57. 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

58. 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!

59. 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

60. 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

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

62. Improvement in median FEV1 since 1986
CF Registry, 2015

63. 1986-2015 Median Predicted Survival (5-year increments)44 40 36
Age in Years 32 28
CF Registry, 2015

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

65. 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

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

67. 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!

68. Thank you!

69. References – See Handout

71. Mucus plugging
Normal

72. Normal
Bronchiectasis
Radiopaedia.org

73. Normal lung Bronchiectasis http://mediswww.meds.cwru.edu/ecsample