Title: Cystic Fibrosis: Progress and Challenges Perry Brown, MD Associate Director, Cystic Fibrosis Center
1Cystic Fibrosis Progress and
ChallengesPerry Brown, MDAssociate Director,
Cystic Fibrosis Center of IdahoDirector of
Pediatric Education, Family Medicine Residency of
IdahoClinical Assistant Professor, University of
Washington School of Medicine
2Objectives
- Understand the pathophysiology of CF
- Be able to explain the most recent data on
epidemiology of CF and life expectancy for
patients with CF - Develop familiarity with CF care from a
respiratory therapy perspective - Appreciate the ways that CF can affect many
different body systems - Realize the power of outcomes data and public
reporting in improving disease-specific care
3What is Cystic Fibrosis?
4What is Cystic Fibrosis?
Common response a rare, severe lung disease
that usually is fatal during childhood.
5What is Cystic Fibrosis?
Common response a rare, severe lung disease
that usually is fatal during childhood.
This is not true!!!
6Life Expectancy in Cystic Fibrosis
- Era Life Expectancy
- 1930sCF first described
- Late 1950sAggressive approach with abx 3.9
years - 1966-1975 12.8 years
- 1975-1984 22.8 years
- 2006 37.2 years
- Bottom line I tell families of infants newly
diagnosed with CF that our goal is no longer
putting off death as far as we can our goal is
maximizing health and function so that quality of
life is high after a cure is found.
7Median Predicted Survival Age, 1985-2006 (with 95
percent confidence bounds)
42
40
38
36
34
Median Survival Age (Years)
32
30
28
26
24
'85
'86
'87
'88
'89
'90
'91
'92
'93
'94
'95
'96
'97
'98
'99
'00
'01
'02
'03
'04
'05
'06
Year
The median predicted survival is 36.9 years for
2006. This represents the age by which half of
the current CF Registry population would be
expected to be dead, given the ages of the CF
patients in the Registry and the mortality
distribution of the deaths in 2006. The whiskers
represent the 95 percent confidence bounds for
the survival estimates, so the 2006 median
predicted survival is between 34.4 and 41.4
years.
8Survival by Birth Cohort
100
2000-2004
98
1995-1999
96
1990-1994
94
92
1985-1989
Percent Surviving
90
88
86
84
1980-1984
82
80
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Age (Years)
Actual survival of CF patients in the Registry
has steadily improved since 1980. Of patients
born between 1980 and 1984 (the earliest cohort
shown here), 90.2 percent survived to age 15.
For patients born between 1990 and 1994, 95.2
survived to age 15.
9Age Distribution of the CF Patient Population,
2006
1,000
100
800
80
600
60
Cumulative Percent
Number of CF Patients
400
40
200
20
0
0
0
10
20
30
40
50
60
70
Age (Years)
Number of CF Patients
Cumulative Percent
The median age is 16.2 years. 45 of patients
are 18 y.o.
10Introduction
- One of the most common fatal genetic disorders in
the US - Classic diagnostic triad elevated sweat Cl-,
pancreatic insufficiency, and chronic pulmonary
disease (as always in medicine, its not this
simple!!!) - Cause defect in a single gene on chromosome 7
that encodes a chloride channel called the cystic
fibrosis transmembrane regulator (CFTR) - There is some blurring of the borders of what
constitutes a true CF diagnosis
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13Effect of Defective CFTR
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15Genetics and Epidemiology
- CF is autosomal recessive
- Incidence of CF
- Caucasians 1 in 2,500 (1 in 29 are carriers)
- Latinos 1 in 9,000 (1 in 46 are carriers)
- African Americans 1 in 15,000 17,000 (1 in 65
are carriers) - Asians 1 in 32,000 90,000 (1 in 90 are
carriers) - More than 1500 different mutations of the CF gene
have been identified numerous other
polymorphisms have also been identified - Most common is delta-F508 deletion of
phenylalanine at position 508 of this protein.
This accounts for 70 of alleles in the U.S. - Different alleles convey different severities of
illness - Modifier genes affect severity of illness among
identical genotypes
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18Diagnosis
- Many diagnoses now result from newborn screening,
with measurement of immunoreactive trypsinogen
(IRT) - Will talk more about this shortly
- Three options for testing for CF
- Sweat chlorideleast expensive, but very
dependent upon technique and lab - Diagnosis requires positive sweat chloride x 2,
plus either appropriate clinical presentation or
positive family history - Need to collect at least a certain minimum volume
of sweat thus, this test is not ideal for babies
under 1 m.o., due to their poor ability to sweat. - False positives certain disease processes, some
normal adults - False negatives CF with malnutrition and/or
edema - Genotypeeasiest, but more expensive. Different
labs check for different numbers of alleles - Most labs test for about 80 alleles, which covers
about 95 of the incidence of all CF alleles - Negative genotype does NOT rule out CF
- Nasal epithelial potential differencemost
technically difficult, uncomfortable, requires
significant cooperation ( 8 y.o. usually), only
offered in a few centers around the country
19Prenatal Screening
- ACOG Parent CF Carrier Screening should be
offered to all pregnant couples - Give stronger consideration to testing if
- Either parent has a relative with CF, or
- Either parent has a relative who is known to have
a CF gene mutation - and
- Parents would consider amniocentesis or CVS to
help decide about continuing the pregnancy or to
help prepare for the birth of a baby with CF, if
both parents were found to be CF carriers - Prenatal testing
- DNA testing
- Amniotic fluid
- Chorionic villus
20Newborn Screening
- Unless CF is diagnosed prenatally or the infant
has meconium ileus, CF diagnosis is often delayed
for months or years (avg. 14.5 m.o.) - The newborn screening test measures trypsin
- Enzyme produced in the pancreas that is
transiently elevated in the blood of
pancreatic-insufficient CF infants at birth
(returns to nl by 3 m.o.) - Detected by immunoreactive trypsinogen (IRT)
testing of neonatal dried blood spots - An elevated IRT on two screening specimens is an
indication for diagnostic workup - Elevated IRT x 2 is not diagnostic of CF
- 2/3 of positives are false-positives!
- Babies with meconium ileus may not have an
elevated IRT, so this finding should lead to
definitive testing for CF regardless of the IRT
result. - About 5 of babies with CF, who are pancreatic
sufficient, will not have an elevated IRT - Normal newborn screen does not rule out the need
for CF workup! - Confirmation Required!!!
- Gold standard sweat chloride test by a
nationally standardized method - Alternative DNA mutation analysis of the CFTR
gene
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22CF Lung Disease
- Pseudomonas aeruginosa has long been the dreaded
bacterium of CF - It can be eradicated temporarily when caught
early into colonization - It cannot be eradicated once it has become
chronically present and entrenched - Mucoid variants are prognostically worse than
those that are non-mucoid - The most feared bacterium currently in CF is
Burkholderia cepacia - Other infectious agents of lungs in CF include
fungi, atypical mycobacteria, and viruses - Emerging pathogens Stenotrophomonas
maltophilia, Achromobacter xylosoxidans,
Scedosporium.
23Age Specific Prevalence of Respiratory
Infections in CF Patients, 2006
100
P. aeruginosa
80
Any Staph
60
Percent of Patients
S. aureus
40
H. influenza
MRSA
20
B. cepacia
S. maltophilia
0
0 to 1
2 to 5
6 to 10
11 to 17
18 to 24
25 to 34
35 to 44
45
Age (years)
P. aeruginosa 55.0
H. influenza 16.9
B. cepacia complex 2.9
S. aureus 51.5
S. maltophilia 12.6
MRSA 18.9
Any Staph 63.5 (S. aureus and/or MRSA)
24CF Lung Disease
- Therapies
- Frequent, high dose antibiotic use
- Chronic intermittent use of inhaled Tobramycin
- Aggressive airway clearancethis is not optional
during inpatient stays!!! - Mucolytics (i.e., DNAse, 7 hypertonic saline)
- Bronchodilators
- Anti-inflammatory medications
- Ibuprofen
- Azithromycin
- Complications
- Respiratory failure
- Hemoptysis
- Spontaneous pneumothorax
25Hypertonic Saline
- Australia, 2004 multicenter, randomized,
double-blind trial, compared inhalation of 4 mL
hypertonic saline (7) to normal saline (0.9)
BID x 12 mths - Improvement (vs. placebo) in FEV1 (p0.039)
- Improvement (vs. placebo) in number of pulmonary
exacerbations - Similar evidence from other, shorter term trials
26Azithromycin
- Hypothesis anti-inflammatory
- Studies
- 2002 (Wolter et. al., Thorax Equi et. al.,
Lancet) - 2003 (Saiman et. al, JAMA)
- 24-week prospective study
- Exclusion criteria
- Less than 6 years of age
- Not chronically infected with P. aeruginosa
- Infected with B. cepacia
- Chronic liver disease
- Positive AFB culture for NTM
- Results
- predicted FEV1 relative change was 6.2
percent - Weight Relative change was 0.8 kg.
- pulmonary exacerbations
- 40 reduction in courses of antipseudomonal
antibiotics - 47 reduction in days in the hospital
- Quality of life trends toward improvement in
quality of life
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28Methods of Airway Clearance
- Chest physiotherapy with postural drainage
- The Vest
- Active Cycle of Breathing
- Flutter Valve / A Capella
- PEP
- Exercise?
- Subwoofers???
- No good studies have documented that one form of
airway clearance is better than another, so long
as airway clearance is done frequently and
regularly - CF patient who is at baseline 30 minutes,
BID - CF patient who is worse than baseline 30
minutes, TID - QID - Recent study undertaken to determine which method
is best - Patients randomized to different methods
- Too many patients left their assigned method to
return to the vest - Differential efficacy could not be determined,
though desirability of method certainly could be
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31Primary Airway Clearance Techniques, by Age Group
100
80
Percent
60
40
20
0
2 to 6
6 to 11
11 to 17
18 to 25
25 to 35
35 to 45
45
Overall
None
Vest
Postural drainage
OscPEP/PEP
Exercise
Forced expiration
Other
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33Infection Control
- MAJOR ISSUE IN CF
- Time-consuming and frustrating for patients
- Time-consuming and frustrating for parents
- Time-consuming and frustrating for doctors and
nurses - Very time-consuming and frustrating for RTs
- Patients are impaired by their co-morbid CF
conditions (malabsorption / malnutrition,
intestinal obstructions, etc.) patients die from
their chronic lung infections, and the
microbiology of these infections is directly
correlated with rate of pulmonary function loss - Hospitals and clinics are the 1 source of
resistant and significantly pathologic organisms
(and Im not talking about the doctors)
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39Hemoptysis in CF
- Minor Hemoptysis (Blood Streaking)
- Common in CF. No specific treatment required
- Persistent streaking may indicate a pulmonary
exacerbation, required antibiotics - Major Hemoptysis (Major Bleed)
- Acute bleeding of a large amount of blood
(formally, more than 240 cc / 24 hrs., or more
than 100 cc / day for more than 3 7 days) - Almost never occurs at under 16 y.o.
- Almost always due to bronchial artery bleeding
(not pulmonary artery) - The vast majority of major bleeds in CF patients
are acute and self-limited - If treatment required, treatment of choice is
bronchial artery embolization by interventional
radiology
40Median Percent Predicted FEV1 vs. Age, 1990 and
2006
100
90
80
Percent Predicted
70
1990
2006
60
50
40
6
8
10
12
14
16
18
20
22
24
26
28
30
Age (Years)
Median FEV1 has improved 10 percentage points at
all ages from 6 to 30 since 1990.
41Lung Transplant Is No Panacea
2005 data
42Is Cystic Fibrosis Just A Lung Disease?
- No!
- Virtually all systems in the body are somehow
affected, other than the neurological and
vascular systems
43CF Upper Airway Disease
- Chronic pansinusitis
- Radiographic changes are constantly present
- Only treat with antibiotics if symptomatic
- Same microbiology as the lunguse the same
antibiotics - Nasal polyposis
- Allergic rhinitis
44CF Pancreatic Disease
- Pancreatic insufficiency
- Patients who are initially pancreatic sufficient
often gradually become insufficient over time - Pancreatitis
- occurs much more commonly in pancreatic
sufficient patients than in insufficient patients - CF related diabetes mellitus
- Often brought on by acute illness, pregnancy,
steroid use, other physiologic stresses
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46Management of Pancreatic Insufficiency
- Most common pancreatic enzyme brands Creon,
Ultrase, Pancrease, Pancrecarb - High calorie, high fat diet is often necessary,
especially in the face of CF with pancreatic
insufficiency - Supplement vitamins A, D, E, and K (ADEK or
Vitamax)
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48Nutritional Hyponatremia
- All babies who are not yet on a full baby-food or
solid diet need sodium supplementation to avoid
hyponatremic complications - Dose Sodium Chloride 2 4 mEq / kg body weight
/ day - May give QD or divide BID
- Can use table salt for sodium chloride source
- ¼ tsp 12 mEq
- Most important in breast-fed infants however,
recent research supports doing this in
formula-fed infants, also - Should check electrolyte status Q 1 3 mths
until on full baby-food or solid diet
49CF Intestinal Disease
- Failure to secrete chloride, and therefore water
into the lumen, results in severely thickened and
sometimes inspissated fecal contents this can
sometimes be counterbalanced by the steatorrhea
from pancreatic insufficiency. - Meconium ileus / meconium peritonitis
- 37 wks gestation ? almost always CF
- DIOS (distal intestinal obstruction syndrome)
- Intussusception (due to lead point of adherent,
inspissated stool) - Rectal prolapse can result from malnutrition and
secondary poor tissue quality, along with
abnormal stools. - Treatment reduce the prolapse, improve
nutrition and stool quality with pancreatic
enzymes, laxatives, and extra calories. Surgery
rarely needed.
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51CF Hepatobiliary Disease
- Gall bladder disease (cholelithiasis,
cholecystitis, microgallbladder) is common - Progressive liver disease can occur
- Cirrhosis in 1 3
52CF Sexual Disease
- Congenital bilateral absence of the vas deferens
(CBAVD) - Almost universal in CF
- Results in azoospermia, and male infertility
- Female relative infertility
- Mainly due to thickened cervical and endometrial
secretions, impairing fertilization and
implantation
53CF Joint and Bone Disease
- CF Reactive Arthritis
- Must be differentiated from other causes of
arthritisJRA, SLE, infectious, etc. - Can present very impressively, with pain,
swelling, warmth, erythema, purpura, etc. - Treatment
- High dose NSAIDsibuprofen vs. naproxen
- Steroid burst vs. taper if necessary (usually
symptoms melt away rapidly) - Osteopenia, osteoporosis, pathologic fractures
- Mostly an issue of adults
- Guidelines for evaluation and care still being
developed
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55- The Promise of the Future
- 33 drugs in the pipeline
- Only 5 of these currently
- available
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57CFF Patient Registry
- 1966 Registry started
- 1975 First internal report
- 1984 First published summary report
- 1999 Center-specific reports
- 2006 Data transparency
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62Intent of Public Reporting
- Advancing the partnership between patients,
families and care centers - Facilitate learning between centers
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