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

Throat Culture 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