Cystic Fibrosis: A MultiDisciplinary Perspective on Issues Facing MUSC Patients

1
Cystic Fibrosis A Multi-Disciplinary Perspective
on Issues Facing MUSC Patients

• Dr. Patrick Flume, MD
• Susan Gray, RN, MSN
• Dr. Lisa King, PharmD
• Dr. Jason Sarashinsky, PharmD

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CF is a Genetic Disease-autosomal recessive-
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Cystic Fibrosis Foundation Consensus Statement

• Diagnosis of CF
• One or more characteristic phenotypic features,
  or
• A history of CF in a sibling, or
• A positive newborn screening test, plus
• Evidence of a CFTR abnormality

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The Sweat Gland
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Sweat Test for Cystic Fibrosis
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Complications of Cystic Fibrosis

• Pulmonary
• chronic airways infection
• bronchiectasis
• Sinuses
• chronic sinusitis
• Pancreatic
• enzyme deficiency
• malabsorption
• diabetes mellitus

• Gastrointestinal
• GERD
• bowel obstruction (DIOS)
• Hepatobiliary
• biliary cirrhosis
• cholelithiasis
• Genito-urinary
• infertility (CBAVD)

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Pathogenesis of CF Lung Disease
CF Gene Mutations
CFTR Dysfunction
Ion Transport Abnormalities
Altered Airway Secretions
Vicious cycle
Infection
Inflammation
Tissue Damage
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Incidence of Major Airway Pathogens by Patient Age
FitzSimmons J Pediatr 122 1-9 1993
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The Vicious Cycle Obstruction, Infection, and
Inflammation
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Progression of CF Airways Disease
100
After treatment
80
60
FEV1 ( predicted)
40
Exacerbations
20
0
Age (y)

• Acute exacerbations with some reversibility
• Chronic decline

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What is an exacerbation?

• Increased cough
• Increased sputum
• Change in sputum (more purulent, hemoptysis)
• Decline in lung function (spirometry)
• New infiltrate on CXR
• Fever, chest pain
• Decreased appetite
• Loss of weight

15
Progression of CF Airways Disease
100
After treatment
80
60
FEV1 ( predicted)
40
Exacerbations
20
0
Age (y)

• Acute exacerbations with some reversibility
• Chronic decline

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Theoretical CF Survival Curves
1.0
P aeruginosa Negative
0.75
Proportion Surviving
0.5
P aeruginosa Positive
0.25
0
0
5
10
15
20
25
30
35
Age (y)
Data compiled from Cystic Fibrosis Foundation
Patient Registry, 19961999.
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Median Age of Survival in CF
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Why has Survival Improved?

• Nutrition
• Antibiotics
• Airway clearance techniques
• Center care
• Improved diagnostic measures
• Transplantation

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CF Center Accreditation

• Specific personnel
• Regular team meetings
• Hospital for inpatient care
• Clinic area
• ½-day clinic each week
• Laboratory function
• Sweat test, micro, chemistries, CXR
• RT available 24/7

• 50 pt minimum
• Adult program
• Age appropriate care
• Submission of annual report, Registry Data,
  Periodic Status Report
• Consultation available
• Referral plan
• transplant

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Cystic Fibrosis Foundation
MUSC Cystic Fibrosis Center
Pediatric CF Program
Adult CF Program
Components of a CF Center Clinical
care Teaching Research
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The MUSC Experience

• 1958 Crippled Childrens Hospital Svc.
• 1978 Multidisciplinary Team approach
• 1993 Adult CF Center established
• 2004 Quality Improvement focus

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The CF Team
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MUSC Center Statistics
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MUSC CF Patients
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New Diagnoses of CF (US)
Year 2001 2002 2003
New Dx 1,013 972 958

• Total number 21,742
• CFF Patient Registry, 2003

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American College of Obstetricians and
Gynecologists
ACOG now recommends that ob-gyns make DNA
screening for cystic fibrosis available to all
couples seeking preconception or prenatal care
not just those with a personal or family history
of carrying the CF gene, as previously
recommended.
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Newborn Screening in SC
Phenylketonuria (PKU) Congenital
hypothyroidism Galactosemia Hemoglobinopathy
Disorders and Traits Congenital adrenal
hyperplasia Medium chain acyl-CoA dehydrogenase
deficiency
and nowcystic fibrosis
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Transition
Adult
Adolescent
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MUSC Method of Transition

• New patient phase
• all new patients meet adult team as early as
  possible
• Reinforcement phase
• adult team meets with teen at age 14
• parents are out of the room for part of
  subsequent clinic visits
• The Transfer
• all care is transferred to adult team
• summer following 18th birthday

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Criteria for Successful Transition

• Commitment
• Preparation
• Timing
• Coordination

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Pulmonary and Nutritional Management

• Overall goals of therapy
• Mobilize secretions
• Control the infection-inflammation cycle
• Improve nutritional status of patient to improve
  growth

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Progression of CF Airways Disease
100
After treatment
80
60
FEV1 ( predicted)
40
Exacerbations
20
0
Age (y)

• Acute exacerbations with some reversibility
• Chronic decline

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Chronic Management

• Respiratory Therapy
• Anti-inflammatory measures
• Nutrition
• Diabetes

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Respiratory Therapy

• Airway clearance techniques
• Beta-agonists
• Albuterol MDI or hand held nebulizer
• Mucolytics
• rhDNase (Pulmozyme)
• Reduces viscosity of sputum
• May lower incidence of pulmonary exacerbations

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Anti-Inflammatory Therapy

• Chronic bacterial infection is stimuli for
  inflammation
• Goal of therapy
• Decrease rate of decline in pulmonary function
• Oral corticosteroids
• Inhaled corticosteroids
• Ibuprofen
• Macrolides (Azithromycin)

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Antimicrobial Theories

• Bacterial colonization vs. pathogen
• Do we treat all infections?
• Non-bacterial causes of exacerbation
• Allergens, viral infections, air pollutants
• Antibiotics are used to improve or delay decline
  in pulmonary function

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Antimicrobial Theories

• Indications for Antibiotic Use
• Prevent colonization of chronic P. aeruginosa
  bacteria
• Maintenance therapy slows decline in pulmonary
  function
• Intense regimens relieve symptoms and restore
  baseline pulmonary function

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First Query

• What are the most common bacterial pathogens
  isolated from respiratory secretions in an adult
  patient?
• Staphylococcus aureus
• Haemophilus influenzae
• Pseudomonas aeruginosa
• Others
• Burkholderia cepacia
• Stenotrophomonas maltophilia

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Chronic Suppressive Antibiotic Therapy

• Inhaled Antibiotics
• Improves drug delivery and decreases systemic
  toxicity while improving overall lung function
• Tobi
• Significant, sustained improvement in pulmonary
  function
• Colistin
• Different mechanism of action, but efficacy is
  still being studied
• Gentamicin (seen in pediatrics)

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Long-term Intermittent Inhaled Tobramycin in
Cystic Fibrosis
On Drug
On Drug
On Drug
16
14
12
10
TSI(n 2571)
8
6
Mean Relative Change in FEV1 Predicted
11.9 p 4
2
0
Placebo (n 2621)
-2
-4
-6
0
2
4
6
8
12
16
20
24
Week
Ramsey BW, et al. N Engl J Med. 19993402330.
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Antibiotic Use in CF Disease

• Outpatient versus Inpatient
• Appropriate if exacerbation is mild and pathogens
  are sensitive
• S. aureus treated with cephalosporins
• P. aeruginosa treated with fluoroquinolones

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Antibiotic Use in CF Disease

• IV antibiotics (Inpatient Management)
• Initial selection is empiric for pathogen and
  patient age
• Treatment of P. aeruginosa
• Aminoglycoside Beta-lactam antibiotic
• Higher doses to compensate for kinetic changes
  (Increased Vd, altered renal clearance)

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Antibiotic Therapy

• Beta-Lactams
• Aminoglycosides
• Tobramycin first line
• Quinolones
• Ciprofloxacin first line
• Meropenem
• Ticarcillin
• TMP-SMX
• Vancomycin (MRSA colonization)

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Nutrition

• Essential part of treatment plan
• Monitor growth (height and wt)
• CF patients have increased caloric needs
• 30-50 greater requirements
• Increased energy expenditure
• Decreased appetite

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Nutritional Goals

• Increased caloric intake
• Increase food intake (no restrictions)
• Dietary supplements (Boost, Ensure)
• Tube feedings overnight
• Parenteral nutrition for short term use
• Reduce Malabsorption
• Enzyme supplementation
• Vitamin supplementation
• Multivitamins
• ADEK

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Pancreatic System

• Primary source of digestive enzymes and insulin
  production
• Blockage of exocrine outflow prevents enzyme
  release- pancreas slowly digests itself
• Malabsorption of fats, proteins, carbohydrates,
  fat soluble vitamins
• Complications
• Numerous foul smelling stools
• Altered appetite and growth retardation
• Abdominal distension
• Diabetes Mellitus

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Pancreatic Enzyme Supplements

• 90 of patients need supplementation
• Contain lipase, amylase, protease
• Individualized doses
• Titrate based on signs of fat malabsorption
• Frequency of stools, steatorrhea, abdominal
  cramping, degree of fullness
• Excess amounts of enzyme leads to constipation

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Pancreatic Enzyme Supplements

• Microencapsulated microspheres
• pH sensitive, protect from gastric acid
  degradation
• Infants/ Children
• Open capsules and sprinkle beads on applesauce,
  rice cereal or baby food
• Feeding tubes
• Pt may take by mouth before tube feeds started
• Do not substitute products
• No generic substitutions

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Cystic Fibrosis Related Diabetes (CFRD)

• Major complication with older CF patients
• Exocrine obstruction prevents insulin secretion
• Patients develop more insulin receptor sites, but
  with decreased affinity for insulin
• 15-40 of pt 35 y/o require insulin
• Associated with increased morbidity and mortality

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Diabetic Glucose Control

• Treat aggressively with insulin
• Nutritional management
• Close attention to timing of meals
• Fasting hyperglycemia and ketosis uncommon
• Basal insulin secretion still functional
• Short acting insulin (ie. Novolog) prior to meals
• Monitoring
• Home glucose testing
• Hemoglogin A1c

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Complications of Cystic Fibrosis

• Pulmonary
• chronic airways infection
• bronchiectasis
• Sinuses
• chronic sinusitis
• Pancreatic
• enzyme deficiency
• malabsorption
• diabetes mellitus

• Gastrointestinal
• GERD
• bowel obstruction (DIOS)
• Hepatobiliary
• biliary cirrhosis
• cholelithiasis
• Genito-urinary
• infertility (CBAVD)

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Treatment of CF Airways Disease

• Remove secretions/reduce obstruction
• Reduce inflammation
• Treat infection
• Address other complicating features
• nutrition
• diabetes mellitus
• GERD
• sinusitis

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Medication and Therapy Counter 0
54
Lung Bronchodilator (Albuterol)
Medication and Therapy Counter 1
55
Lung Bronchodilator (Albuterol) Pulmozyme
Medication and Therapy Counter 2
56
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI
Medication and Therapy Counter 3
57
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline
Medication and Therapy Counter 4
58
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques
Medication and Therapy Counter 5
59
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Medication and Therapy Counter 6
60
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation
Medication and Therapy Counter 7
61
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Medication and Therapy Counter 8
62
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins
Medication and Therapy Counter 9
63
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin
Medication and Therapy Counter 10
64
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks
Medication and Therapy Counter 11
65
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen
Medication and Therapy Counter 12
66
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid
Medication and Therapy Counter 13
67
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
Medication and Therapy Counter 14
68
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
AM X
noon
PM
bedtime
TIME 10 min
PILLS
69
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
AM X X
noon
PM
bedtime
TIME 20 min
PILLS
70
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
AM X X X
noon
PM
bedtime
TIME 40 min
PILLS
71
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
AM X X X X
noon
PM
bedtime
TIME 1 hr 10 min
PILLS
72
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
AM X X X X X
noon
PM
bedtime
TIME 1 hr 20 min
PILLS
73
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
AM X X X X X X
noon
PM
bedtime
TIME 1 hr 20 min
PILLS
74
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
AM X X X X X X X
noon
PM
bedtime
TIME 1 hr 20 min
PILLS 4
75
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
AM X X X X X X X X
noon
PM
bedtime
TIME 1 hr 20 min
PILLS 5
76
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
AM X X X X X X X X X X
noon
PM
bedtime
TIME 1 hr 30 min
PILLS 5
77
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
AM X X X X X X X X X X
noon X X X X
PM X X X X X X
bedtime X X X X X X X X X
TIME 4 hr
PILLS 14
78
Lung Bronchodilator (Albuterol) Pulmozyme
TOBI Hypertonic saline Airway clearance
techniques Sinuses Nasal steroids (Flonase)
Nasal irrigation Pancreas Digestive enzymes
Multivitamins Insulin Glucose checks Etc.
Ibuprofen Ursodeoxycholic acid Acid
suppression (Prevacid/Zantac)
AM X X X X X X X X X X X X X
noon X X X X
PM X X X X X X X X
bedtime X X X X X X X X X X X X
TIME 4 hr
PILLS 25