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Update on Newborn Screening for Cystic Fibrosis. Jacquelyn Zirbes, DNP, RN, CNP, CCRC Stanford University Cystic Fibrosis Center Lucile Packard Children’s Hospital. Discovery of the ∆F508 CFTR Mutation Research teams led by Lap-Chee Tsui, Jack Riordan, and Francis Collins.

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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

slide2

Discovery

of the ∆F508

CFTR Mutation

Research teams led byLap-Chee Tsui, Jack Riordan,

and Francis Collins

newborn screening definition
Newborn Screening Definition *
  • Population-based public health program applying preventivemedicine in defined regions to reduce infantmorbidity 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-upsystems.

Allen and Farrell (1996). Adv Pediatrics 43: 231-270

Allen 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

Death

Life Threatening

Or Irreversible

Disease

Biologic

Onset

Birth

Symptomatic

Onset

Preclinical Stage

Time/Event

slide7

Diagnosis Through Newborn Screening

This ~0.4 ml dried blood specimen supports numerous screening tests!

slide8

NBS State Program:

Positive Screen

Primary Care Provider

CF Center

Dedicated Line

NBS Coordinator

Family

california 4 step cf nbs model
California 4-Step CF NBS Model
  • Immunoreactive Trypsinogen assay (cut-off = 1.6%; projected sensitivity= 95.7%)
  • DNA analysis with a panel of 40 CFTR mutations (15/23 ACMG* mutations + “minority” alleles)
  • DNA scanning  sequencing by Ambry
  • Sweat test when 2 or more mutations detected
california 4 step method s goals
California 4-Step Method’s Goals
  • Use initial dried blood specimen only
  • Focus on “severe” cases of cystic fibrosis
  • Identify at least 90% of Hispanic, White, and Black cases
  • Reduce burden of false positives & negatives, sweat tests, and costs
  • Achieve efficient reporting of NBS test results
  • Follow-up and diagnosis of positive screens at CF Centers
screening diagnosis
SCREENING ≠ DIAGNOSIS

(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.”

Hennekens and Buring, Epidemiology in Medicine, p327

california minimum guidelines
California 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 results
Updated California Results
  • 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

* Zielenski J and Tsui LC, Ann Rev Genet 1995; 29:777-807

ca cf nbs collaborative network
CA CF NBS Collaborative Network
  • 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
advisory board
Advisory Board

Frank Accurso, MDUniversity of Colorado

Phil Farrell, MD, PhDUniversity of Wisconsin

Paul Quinton, PhDUniversity of California San Diego

Jeff Wine, PhDStanford University

specific aims
Specific Aims

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
study outcome measures
Study Outcome Measures

-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.

study outcome measures26
Study Outcome Measures

Secondary Outcomes

Serum 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

study entry criteria
Study entry criteria

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 protocol
Study Protocol

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

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)

slide31
Initiate CF center care in newborns

Provide genetic counseling

Prevent severe malnutrition

• Vitamin E deficiency (hemolytic anemia)

• Vitamin A deficiency

• Essential fatty acid deficiency

• Protein energy malnutrition*

• Growth failure

Prevent hyponatremia/hypochloremia

• Salt loss in sweat*

• Associated with breast feeding

Prevent 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

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.

the 21st century is a new 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

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
slide36

The Stanford Cystic Fibrosis Center at Lucile Packard Children’s Hospital

  • Individual Treatment Plan
  • Collaborative Care
  • Interdisciplinary Team
  • Standards of CF Care
  • Family Centered Care
  • Emphasis on Family and Primary Provider Education
  • Research