update on newborn screening for cystic fibrosis jacquelyn zirbes, dnp, rn, cnp, ccrc stanford...
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Update on Newborn Screening for Cystic
Fibrosis
Update on Newborn Screening for Cystic
Fibrosis
Jacquelyn Zirbes, DNP, RN, CNP, CCRC
Stanford University Cystic Fibrosis Center
Lucile Packard Children’s Hospital
Jacquelyn Zirbes, DNP, RN, CNP, CCRC
Stanford University Cystic Fibrosis Center
Lucile Packard Children’s Hospital
Discoveryof the ∆F508CFTR Mutation
Research teams led byLap-Chee Tsui, Jack Riordan,and Francis Collins
Newborn Screening Definition *Newborn Screening Definition *
• Population-based public health program applying preventive medicine in defined regions to reduce infant morbidity and mortality from certain biochemical and genetic disorders by using presymptomatic detection/diagnosis with dried blood specimens from newborns analyzed in central laboratories employing automated procedures linked to clinical follow-up systems.
• Population-based public health program applying preventive medicine in defined regions to reduce infant morbidity and mortality from certain biochemical and genetic disorders by using presymptomatic detection/diagnosis with dried blood specimens from newborns analyzed in central laboratories employing automated procedures linked to clinical follow-up systems.
Allen and Farrell (1996). Adv Pediatrics 43: 231-270Allen and Farrell (1996). Adv Pediatrics 43: 231-270
Principles of Achieving Better Outcomes Through Newborn
Screening
Principles of Achieving Better Outcomes Through Newborn
Screening
Screening/Follow-up Diagnosis
Effective Therapy
Birth BiologicOnset
SymptomaticOnset
Life ThreateningOr Irreversible Disease
Death
Preclinical Stage
Time/Event
This ~0.4 ml dried blood specimen supports numerous screening tests!
Diagnosis Through Newborn Screening
NBS State Program:Positive Screen
Primary Care Provider
Family
CF CenterDedicated Line
NBS Coordinator
California 4-Step CF NBS Model California 4-Step CF NBS Model
1. Immunoreactive Trypsinogen assay (cut-off = 1.6%; projected sensitivity= 95.7%)
2. DNA analysis with a panel of 40 CFTR mutations (15/23 ACMG* mutations + “minority” alleles)
3. DNA scanning sequencing by Ambry
4. Sweat test when 2 or more mutations detected
1. Immunoreactive Trypsinogen assay (cut-off = 1.6%; projected sensitivity= 95.7%)
2. DNA analysis with a panel of 40 CFTR mutations (15/23 ACMG* mutations + “minority” alleles)
3. DNA scanning sequencing by Ambry
4. Sweat test when 2 or more mutations detected
California 4-Step Method’s Goals California 4-Step Method’s Goals
1. Use initial dried blood specimen only2. Focus on “severe” cases of cystic
fibrosis3. Identify at least 90% of Hispanic, White,
and Black cases4. Reduce burden of false positives &
negatives, sweat tests, and costs5. Achieve efficient reporting of NBS test
results6. Follow-up and diagnosis of positive
screens at CF Centers
1. Use initial dried blood specimen only2. Focus on “severe” cases of cystic
fibrosis3. Identify at least 90% of Hispanic, White,
and Black cases4. Reduce burden of false positives &
negatives, sweat tests, and costs5. Achieve efficient reporting of NBS test
results6. Follow-up and diagnosis of positive
screens at CF Centers
SCREENING ≠ DIAGNOSISSCREENING ≠ DIAGNOSIS
(exception: DF508 /DF508 = CF)(exception: DF508 /DF508 = CF)
Definition of “Screening for Early Detection of Disease”Definition of “Screening for Early Detection of Disease”
“The screening procedure itself does not diagnose illness.”
“Those who test positive are sent for further evaluation by a subsequent diagnostic test or procedure to determine whether they do in fact have the disease.”
“The screening procedure itself does not diagnose illness.”
“Those who test positive are sent for further evaluation by a subsequent diagnostic test or procedure to determine whether they do in fact have the disease.”
Hennekens and Buring, Epidemiology in Medicine, p327
California Minimum GuidelinesCalifornia Minimum Guidelines
1. Preparation for Sweat Chloride Test
2. Sweat Chloride Test
3. Laboratory testing at first CF Center visit
4. Family Studies
5. Interpretation of Sweat Chloride Test Results
Updated California ResultsUpdated California Results
• 210 infants identified • 13 CF Centers• 27 LPCH
• 210 infants identified • 13 CF Centers• 27 LPCH
ΔF508/ ΔF508
1
ΔF508/other
18
other/other
8
Genotype-Phenotype Relationships*
Genotype-Phenotype Relationships*
General Principle: genotype determines phenotype (e.g., pancreatic insufficiency vs sufficiency in
CF)
But, gene modifiers and extrinsic factors contribute also
In metabolic disorders such as PKU, mild (non-classical) cases can occur
In CF, genotype alone does not determine the pulmonary phenotype
General Principle: genotype determines phenotype (e.g., pancreatic insufficiency vs sufficiency in
CF)
But, gene modifiers and extrinsic factors contribute also
In metabolic disorders such as PKU, mild (non-classical) cases can occur
In CF, genotype alone does not determine the pulmonary phenotype
* Zielenski J and Tsui LC, Ann Rev Genet 1995; 29:777-807
California Genetic Disease Screening Program Children’s Hospital of Central California Children’s Hospital of Los Angeles Children's Hospital and Research Center at
Oakland Kaiser Permanente Southern California Loma Linda University Medical Center Miller Children's at Long Beach Memorial
Medical Center Stanford University Sutter Sacramento Medical Center University of California San Diego University of California San Francisco Ventura County Medical Center
Frank Accurso, MDUniversity of Colorado
Phil Farrell, MD, PhDUniversity of Wisconsin
Paul Quinton, PhDUniversity of California San Diego
Jeff Wine, PhDStanford University
In a well defined cohort of newborns with fully identified CFTR mutations determine:
1. The feasibility of applying a uniform infant preparation protocol for sweat testing that includes salt supplementation and adequate fluid intake guidelines
2. The genotypic determinants of sweat chloride concentration and its longitudinal changes.
3. The effect of fluid and electrolyte balance on sweat chloride results
-Primary Outcome Measure Sweat chloride concentration at
diagnosis.
We hypothesize that under the baseline conditions created by the preparation protocol sweat chloride will unequivocally discriminate between varying levels of CFTR dysfunction.
Secondary OutcomesSerum aldosterone, urinary and
serum electrolytes.Serum IRT Longitudinal changes in sweat
chloride Longitudinal changes in clinical
parameters during the first 2 years of life to gain
Inclusion criteria: 1) Positive California CF newborn screening result (2
CFTR mutations identified). 2) Post-menstrual age ≥ 36 weeks 3) Age at time of first sweat test ≥ 2 weeks old and ≤
16 weeks old 4) Weight at time of sweat test ≥ 2 Kg
Exclusion criteria:
1) NICU Hospitalization at the time of diagnosis. 2) Requiring IV fluids and/or TPN at the time of test. 3) Diagnosis of hypothyroidism or other
endocrinologic/metabolic abnormality. 4) Presence of any other active medical condition (e.g.
congenital heart, liver, or renal disease) that in the opinion of the CF Center would interfere with reliable sweat testing.
Study participation for approximately 2 years
Patients will be evaluated 5 times over the 2 year period
Family will receive salt supplementation kit (salt packets, instructions and educational material) in anticipation of study visit
VISIT
Pre-Visit
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5
Time PhoneResult
Initial Diagnostic
1 month post visit 1
6 (± 1) mos. old
12 (± 1) mos. old
24 (± 1) mos. old
Salt Kit X X X X X X
Sweat X X X X X
Serum X X X X
Urine X X X X X
Clinical Measures
X X X X X
Micro X X X X
Stool X
Care of the CF Infant Diagnosed after Newborn
Screening
Care of the CF Infant Diagnosed after Newborn
Screening• CF Foundation Consensus Guidelines are still
evolving
• Need to develop a collaborative care model with PCP-subspecialist partnership
• An evidence based medicine strategy is very difficult to develop
• Thus, prudent principles of Dx → Rx based on need should be followed
• Set high standards such as > 50th percentile growth and normal PFT’s
• But, avoid overly aggressive clinical management (primum non nocere)
• CF Foundation Consensus Guidelines are still evolving
• Need to develop a collaborative care model with PCP-subspecialist partnership
• An evidence based medicine strategy is very difficult to develop
• Thus, prudent principles of Dx → Rx based on need should be followed
• Set high standards such as > 50th percentile growth and normal PFT’s
• But, avoid overly aggressive clinical management (primum non nocere)
Initiate CF center care in newbornsProvide genetic counselingPrevent severe malnutrition• Vitamin E deficiency (hemolytic anemia)• Vitamin A deficiency• Essential fatty acid deficiency• Protein energy malnutrition*• Growth failurePrevent hyponatremia/hypochloremia• Salt loss in sweat*• Associated with breast feedingPrevent early progression of lung disease• Recurrent bacterial infections• Obstructive pulmonary disease• Atelectasis with mucus plugs
* Potentially fatal
Initiate CF center care in newbornsProvide genetic counselingPrevent severe malnutrition• Vitamin E deficiency (hemolytic anemia)• Vitamin A deficiency• Essential fatty acid deficiency• Protein energy malnutrition*• Growth failurePrevent hyponatremia/hypochloremia• Salt loss in sweat*• Associated with breast feedingPrevent early progression of lung disease• Recurrent bacterial infections• Obstructive pulmonary disease• Atelectasis with mucus plugs
* Potentially fatal
Goals of CF Early Diagnosis & Treatment
The GI/Nutrition Rationale for NBS
The GI/Nutrition Rationale for NBS
1.CF patients are generally well nourished at birth
2.PI will develop in ~90% of patients by ~1 year
3.Severe malnutrition will develop in ~50% untreated
4.PI can be anticipated and malnutrition prevented
5.Long term benefits of normal nutrition are significant
1.CF patients are generally well nourished at birth
2.PI will develop in ~90% of patients by ~1 year
3.Severe malnutrition will develop in ~50% untreated
4.PI can be anticipated and malnutrition prevented
5.Long term benefits of normal nutrition are significant
The Pulmonary Rationale for NBS
The Pulmonary Rationale for NBS
1.The CF lung is normal at birth, but not for long.
2.Lung disease often develops as early as 2 months.
3.Pseudomonas aeruginosa (PA) colonization may occur in ~1/3 of undiagnosed patients.
4.Transformation from PA to mucoid PA is the greatest long term risk for children.
1.The CF lung is normal at birth, but not for long.
2.Lung disease often develops as early as 2 months.
3.Pseudomonas aeruginosa (PA) colonization may occur in ~1/3 of undiagnosed patients.
4.Transformation from PA to mucoid PA is the greatest long term risk for children.
The 21st Century is aNew Era for Children with CF
The 21st Century is aNew Era for Children with CF
• An established trend of early diagnosis through NBS
•A paradigm shift in therapeutic strategy from the 3 I’s to
the 3 P’s
•No longer dominated by intervention in individuals with
illnesses
•But prevention in presymptomatic patients
– Prevention of early deaths
– Prevention of salt depletion
– Prevention of malnutrition and growth failure
– Prevention of “cross-infection”
– Prevention of chronic PA and early mPA
– Prevention of hospitalizations
– Prevention (eventually) of lung disease
• An established trend of early diagnosis through NBS
•A paradigm shift in therapeutic strategy from the 3 I’s to
the 3 P’s
•No longer dominated by intervention in individuals with
illnesses
•But prevention in presymptomatic patients
– Prevention of early deaths
– Prevention of salt depletion
– Prevention of malnutrition and growth failure
– Prevention of “cross-infection”
– Prevention of chronic PA and early mPA
– Prevention of hospitalizations
– Prevention (eventually) of lung disease
Summary of Advantages of CF Newborn Screening
Summary of Advantages of CF Newborn Screening
• Avoid diagnostic quest• Early, specific and proper care• Proactive strategy of care• Prevention• Improved quality of life• Improved parental learning• Reduce costs• Prevent malnutrition and micronutrient deficiencies• Reduce risk of cognitive dysfunction
• Avoid diagnostic quest• Early, specific and proper care• Proactive strategy of care• Prevention• Improved quality of life• Improved parental learning• Reduce costs• Prevent malnutrition and micronutrient deficiencies• Reduce risk of cognitive dysfunction
• Individual Treatment Plan• Collaborative Care• Interdisciplinary Team• Standards of CF Care• Family Centered Care• Emphasis on Family and Primary Provider
Education• Research
• Individual Treatment Plan• Collaborative Care• Interdisciplinary Team• Standards of CF Care• Family Centered Care• Emphasis on Family and Primary Provider
Education• Research
The Stanford Cystic Fibrosis Center at Lucile Packard
Children’s Hospital