Transcript Cystic Fibrosis - University of Arizona Pediatric

Cystic Fibrosis and the Role
of Newborn Screening
Cori Daines, MD
October 6, 2009
Objectives
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Understand the genetics of CF
Recognize how to diagnose CF
Understand newborn screening for CF
Understand the pathophysiology
associated with CF
• Become familiar with the treatments
used in CF
Outline
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Genetics
Incidence
Basic defect
Diagnosis
Newborn Screening
Pathogenesis
Clinical Manifestations
Treatments
Outcomes
Genetics
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Autosomal recessive inheritance
Chromosome 7
Codes for CFTR, a chloride channel
Over 1600 known mutations of the gene
Five classes of mutations: 1--protein
production, 2--defective processing, 3-defective regulation, 4--defective conduction,
5--reduced CFRT production
CFTR Genetics
• CFTR gene:
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q31.2 locus on the long arm of chromosome 7
230,000 base pairs long
CFTR is 1,480 amino acids long
Most common mutation, ΔF508 is a deletion (Δ) resulting in
a loss of the amino acid phenylalanine (F) at the 508th (508)
position on the protein
• Approximately 1:30 Non-hispanic Caucasians are
carriers of a CFTR disease causing mutation
CFTR
Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary
Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.
Classes of Mutations
http://www.cysticfibrosismedicine.com/htmldocs/CFText/genetics.htm
Inheritance
Mother carrier
C
c
C
CC
Normal
Cc
Carrier
c
cC
Carrier
cc
Affected
Father
carrier
Incidence
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1 in 3100 for Caucasians
1 in 9200 for Hispanics
1 in 10,900 for Native Americans
1 in 14,400 for African Americans
1 in 31,000 for Asian Americans
Basic Defect
Diagnosis
• One or more clinical features of CF
PLUS
– Two CF mutations
OR
– Two positive sweat tests
OR
– Abnormal nasal potential difference
Traditional Presentation
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Recurrent Pneumonia
Chronic sinusitis
Nasal polyps
Failure to thrive
Meconium ileus
Dehydration
Hepatitis
Infertility
Diagnostic Testing
• Sweat chloride testing
– Quantitative pilocarpine iontophoresis
• Genetic testing
– Genzyme
– Ambry
• Nasal potential difference
• Newborn screening
Sweat test
http://www.nucleusinc.com
Illustration copyright 2003 Nucleus Communications, Inc.
CF-NBS History
• Multiple techniques evaluated
• Immunoreactive trypsinogen (IRT) on NBS blood spot
testing now standard
• IRT is elevated due to pancreatic duct dysfunction
• IRT is increased in both pancreatic sufficient and
insufficient CF newborns
• Screening first started in Australia (NSW: 1981) and
in USA (CO: 1982)
• 49 states plus DC currently and likely all states by
end of 2010
IRT-DNA NBS Strategy
Sharp JK, Rock MJ. Clinic Rev Allerg Immunol 35:107, 2008.
Wisconsin Cystic Fibrosis
Neonatal Screening Study
• Control Group was diagnosed 15 months later on
average (P<0.001)
• No differences in sex, cf care site, or pancreatic
insufficiency (83%) between groups
• delF508 was more common in Early Diagnosis Group
• Height for age, Weight for age, Head Circumference
percentiles all significantly lower at diagnosis in the
Control Group
• Shwachman–Kulczycki scores significantly lower at
diagnosis in the Control Group (87 vs 92; P<0.006)
primarily due to differences in weight
Farrell PM et al. N Engl J Med 337:963,1997.
Pancreatic Insufficient CF
Patients
Height for Age Percentile
%le
%le
Weight for Age Percentile
NBS vs Control all at least P<0.01 or better
Farrell PM et al. N Engl J Med 337:963,1997.
WCFNSS and Pulmonary
Status
• NBS Group median time to acquisition of P.
aeruginosa (PA) was 3.0 years compared to
6.0 years in the Control Group
– Site of care with increased exposure
– More delF508 in NBS group with PA acquisition
3.5 years earlier than in non-delF508 patients
• Both groups received quality CF care, and
although effective, we cannot prevent decline
in lung function at this time
Newborn Screening: CDC 2004
• Consider state resources/priorities
• Collect follow-up data in collaboration with CF
Centers
• Collaboration between states with optimization of
strategies
• Rigorous infection control practices to prevent early
acquisition of organisms from older patients
• Parent and provider education
• Prompt referral to diagnostic centers
– Skilled in sweat testing
– Counseling to families including false positives
CDC: Risks of CF-NBS
• Infants Affected with CF and Their Families
– Altered Parent-Child Relationships - Not supported
– Person-to-Person Transmission of Infectious Agents – Concern
• Infants with False-Positive CF Screens and Their Families
– Psychological Distress from Screening – Concern
– Misunderstanding of Carrier Status - Concern
– Other Implications to Families of Carrier Identification - Not supported
• Health-Care System
– False-negative results might experience a delay in diagnosis - Concern.
– Diversion of health-care system resources - Concern
False Positives: IRT/DNA
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Wisconsin study of 63 families with positive IRT/DNA test results*
– 6% of families thought that being a
carrier could cause illness
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Wisconsin study of 138 families conducted after CF screening with
positive results**
– Only 2/3rd had genetic counseling from healthcare professional
– 88% understood that their child was a carrier
– 11% either believed that their child would have CF subsequently or did not
know whether that could happen
– 50% felt feeling confused
– Only 25% reported feeling no anxiety about carrier status
– Less than 50% understood that they were at increased risk of having a child
with CF whether or not they received counseling
* Mischler EH et al. Pediatrics 102:44,1998.
** Ciske DJ et al. Pediatrics 107:699,2001.
CFF Guidelines for Newborn
Screening
Farrell PM et al. J. Pediatr 153:S4,2008.
CFF Guidelines for Newborn
Screening
• Caveats
– Infant should be > 2kg and at least 36 weeks
corrected gestation for sweat chloride
determination
– Minimum sweat weight is 75mg per sample
– Two ‘disease causing’ mutations should be
considered diagnostic
– Even with negative sweat chloride
(<29 mmol/l) if two CF mutations are in trans then
diagnosis is strongly suggested
Farrell PM et al. J. Pediatr 153:S4,2008.
CF Disease Causing
Mutations
Farrell PM et al. J. Pediatr 153:S4,2008.
IRT-DNA NBS Strategy
Sharp JK, Rock MJ. Clinic Rev Allerg Immunol 35:107, 2008.
Arizona CF NBS
Program
• Started in November 2007
• IRT/DNA strategy with 46 mutations chosen
to represent ethnic/racial makeup of Arizona’s
population
• Primary care provider based
• Involvement of CF Centers at Phoenix
Children’s Hospital and at the University of
Arizona
Arizona CF NBS
Program
• Specimen screened for IRT with cutoff at
2.2% of values for the day
• Specimens with IRT in the top 2.2% are
screened with a panel of 46 mutations
• Outcomes:
– No mutations:
– One mutation:
– Two mutations:
CF is not indicated
CF may be present
CF is likely
Positive Results
• Primary care provider and family notified of
positive screen by mail/fax
• Regional CF Center notified by fax/email
• CF Centers are responsible for initial followup with PCP to ensure positive screen is
proceeding to sweat testing
• CF Centers notify AzDHS of results of sweat
tests, diagnoses, and care onset
• AzDHS will track down missed cases
IRT + Two Mutations
• CF Center will contact PCP ASAP
• Information for Family and PCP includes
contact information for CF Center as well
• PCP refers for confirmatory sweat testing at
reference laboratory (UMC or TMC)
• CF Center follows up with PCP on parental
notification and sets up a clinic visit
• CF Center sees family and child in CF clinic
with infection control/cohorting
IRT + One Mutation
• CF Center will contact PCP
• PCP refers for diagnostic sweat testing at reference
laboratory (UMC or TMC)
• CF Center follows up results with PCP and
communicates with AzDHS
– If sweat chloride positive, then PCP/CF Center proceed with
notification and setting up care
– If sweat chloride negative, then PCP follows up with family
and counsels them regarding carrier status
• Positive or borderline sweat chlorides with one
mutation will lead to further in-depth genetic testing
conducted in consultation with the regional CF Center
False Positives
• Primary care provider delivers information to
family
– Negative sweat test results
– Carrier status
• No disease (or very, very unlikely)
• Implications for future pregnancies/children
• Family may request genetic testing to determine whether
both parents are carriers similar to carrier detection
situation in pregnant women
• Family may request / PCP may recommend formal
genetic counseling
• Should the child be informed of carrier status
when older?
False Positives
• 1/10 to 1/20 pregnancies have different biological
father than is socially apparent and this has
implications for carrier testing in parents
• Data following up false positives suggests that part of
future routine visits should be to clarify that the child
does not have cystic fibrosis to allay concern
• One mutation does place the child at higher risk such
as idiopathic pancreatitis or congenital absence of
the vas deferens
• The appearance of symptoms suggestive of cystic
fibrosis should lead to consultation and re-testing
AZ CF-NBS Results
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November 1st, 2007 to October 21st, 2008
94,885 samples screened by IRT
~1,900 DNA test samples (top 2.2% IRT)
206 DNA analysis samples with one or two
mutations
AZ CF-NBS Results
• 17 infants diagnosed
– 7 infants were delF508 homozygotes
– 6 infants were compound heterozygotes
– 4 infants were diagnosed with one mutation and
positive sweat chloride
• Average age to first CF clinic: 30 days
• No infants diagnosed since inception of NBS
who were part of NBS program; i.e. false
negatives
Southern AZ Results
• November 1st, 2007 to February 1st, 2009
• 6 children diagnosed with two mutations
• 55 children had only one mutation
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45 children with negative sweat test
2 children with positive sweat test / diagnosis
6 children still being worked up
2 children lost to follow-up – AzDHS referred
• Thus, of 47 children with one mutation and definitive
outcome information, only 2 or 4.3% had cystic
fibrosis
Pathophysiology
CFTR Gene Defect
Defective Ion Transport
Airway surface liquid depletion
Defective mucociliary clearance
Mucus obstruction
Inflammation
Infection
Pulmonary Manifestations
• Chronic symptoms
– Productive cough, wheeze, recurrent
exacerbations
• Obstructive lung disease
• Bronchiectasis
• Infection
Bronchiectasis
From: http://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htm
Infection
Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary
Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.
Sinus Disease
• Develops in most CF patients
• 90-100% of patients older than 8
months develop panopacification of the
paranasal sinuses
• Nasal polyposis in 10-32%
– Associated with chronic inflammation
– Cause obstruction, headache, drainage
– Often require surgery
Pancreatic Disease
• Pancreatic insufficiency at birth in 85%
– Mucus plugging of pancreatic ducts with
autolysis of the pancreas
• Malabsorption
– Failure to thrive
– Fat soluble vitamin deficiencies
• Chronic pancreatitis
• Diabetes
Diabetes
• Occurs in as much as 40% of patients
by adulthood
• Delayed and diminished insulin
response
• OGTT testing starting at age 10 every 2
years
• Insulin therapy for fasting glucose >140
Intestinal manifestations
• Meconium ileus
– 10-20% of infants with CF
– Virtually pathognomonic of CF
• Distal intestinal obstructive syndrome
– Small bowel obstruction due to dehydrated
intestinal contents
• Rectal prolapse
– Straining from too many or too few enzymes
Biliary Disease
• Focal biliary cirrhosis due to inspissated
bile
• Portal hypertension in 2-5% of patients
– May lead to need for liver transplant
• Cholelithiasis in up to 12% of patients
Electrolyte Abnormalities
• Excessive excretion of sodium and
chloride in the sweat
– Basis of sweat test
• Hypochloremic dehydration with
metabolic alkalosis
Reproductive Manifestations
• Men
– Congenital absence of the vas deferens in
97-98%
• Women
– 20% may be infertile
– Secondary amenorrhea
– Tenacious cervical mucus
Other Manifestations
• Osteoporosis, osteopenia
– Increased risk of pathological fractures
• Clubbing
• CF-associated arthropathy
– 2-9% of patients
From: Fawcett et al., 2004
Treatment-Lungs
Gene therapy, potentiators,
activators
CFTR Gene Defect
Defective Ion Transport
Alternative channel
activators
Airway surface liquid depletion
Defective mucociliary clearance
Rehydration
therapy
Airway clearance,
Bronchodilators,
Mucolytics
Mucus obstruction
anti-inflammatory
Inflammation
Infection
Anti-infectives
Exacerbations
• Changes in symptoms and signs from
baseline
– Cough, sputum, lung function, crackles
• Treatment options
– Inpatient IV therapy
– Outpatient IV therapy
– Outpatient Oral therapy
Lung Transplant
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5 year survival slightly better than 50%
New organ allocation system
Controversial for pediatric patients
Expensive, problematic but may be the
only option for some patients
Sinus Disease
• Nasal corticosteroids
• Sinus washes
– Saline
– Antibiotics
• Antihistamines, if allergic
• Surgery
– Polypectomy
– Washes and windows
Pancreatic disease
• Pancreatic Enzyme Replacement
– Given with all meals and snacks
– Dosed according to patient weight, 10002500 Units Lipase/kg body weight
– Assessment: fecal elastase, quantitative
72-hour fecal fat
– Adjunctive use of H2 blockers, PPI’s
– Name-brand only
Nutritional Support
• Specific guidelines
– BMI at 50th% or above
• Supplement fat-soluble vitamins
• Nutritional supplements
– High calorie oral supplements: shakes,
additives
– Tube feedings: Nasogastric, gastrostomy
Diabetes
• Close monitoring
– Yearly OGTT if intolerance noted
– Home glucose monitoring
• Insulin
– Dosed with carbohydrate counting
– Role in growth, lung health
• Limit sugars, not calories
• Closely associated with outcomes
Intestinal Disease
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Hydration
Limit pain medication
Activity
Medications
– Miralax
– Stool softeners
– Golytely
• Enemas, including gastrografin
• Surgery
Biliary Disease
• Ursodiol
– Increases bile flow
– Reduces toxicity of bile acids
• Sclerotherapy, esophageal banding
• Portosystemic shunts
• Liver transplant
Electrolyte Abnormalities
• Hydration
• Addition of salt to diet, especially infant,
especially in summer
Infertility
• Microsurgical or percutaneous
epididymal sperm aspiration
• In vitro technology
• Genetic testing
Other
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Calcium supplements
Osteo
Treatment for anemia
Concurrent diseases
Psychosocial Issues
• Quality of Life
– Hospitalizations, daily therapy burden, morbidity,
limitations
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Normal growth and development
Transitions
Adherence
Financial issues, insurance
Family planning
End of life issues
Teamwork
• Physicians
– Pulmonary, Primary MD, Gastroenterology,
ENT, Surgery, Endocrine, Infectious
Disease, plus
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Nurses
Respiratory Therapist
Nutrition
Social work
Outcomes
Median predicted survival of patients with cystic fibrosis
QuickTime™ and a
decompressor
are needed to see this picture.
Data from Cystic Fibrosis Foundation, 2007.