Cystic Fibrosis Newborn Screening Lori Vanscoy M D

Cystic Fibrosis Newborn Screening Lori Vanscoy, M. D. LCDR, MC, USN National Naval Medical Center December 2007

Courtesy of P. Farrell

Overview • Pathophysiology of Cystic Fibrosis • Newborn Screening – Benefits – Methods of Screening • Evaluation of infant with positive newborn screen

Cystic Fibrosis • Autosomal recessive disorder • CFTR gene on long arm of chromosome 7 • 1: 3200 live births (Caucasians) • Carrier rate for a CFTR mutation 1: 25 • Most patients have no family history

www. hopkinscf. org

Ackerman, NEJM (1997) 336: 1575

www. hopkinscf. org

Median Predicted Survival Age, 1985 -2005 36. 5 years old Median Survival Age (Years) 40 38 36 34 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 Year

Diagnosis • • Meconium ileus Direct hyperbilirubinemia Failure to thrive Recurrent respiratory problems Chronic sinus disease Rectal prolapse Newborn screening Prenatal screening

Potential Benefits of CF NBS • Disease-oriented outcomes – Growth and Nutrition – Lung Function • Patient-oriented outcomes – Survival • Benefits to families – Quality of life – Resource utilization (e. g. hospitalization)

Percent 3 rd of patients less than the percentile for weight * * * p <0. 05 SYMP vs NBS each age range * * * CFF Patient Registry, 2002

Nutrition and Pulmonary Function Are Intertwined 100 FEV 1 Percent Predicted 95 90 85 80 75 70 65 60 55 50 <5 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 BMI Percentile Males Patients 6 to 20 Years Old Females CFF Patient Registry, 2006

Percent predicted FEV 1 2002 CFF Registry * * * p <0. 05 SYMP vs NBS each age range CFF Patient Registry, 2002

Survival from CFF Registry Lai et al. J. Pediatr (2005) 147(3): S 57 -S 63

Risks and Harms of CF NBS • False positives – Increased anxiety – Misunderstanding of information • False sense of security with negative NBS • Possibility of overwhelming available resources – Sweat testing – Genetic counseling • Person-to-person transmission is a potentially dangerous harm – Can be managed by rigorous infection control

Approaches to CF NBS • IRT/IRT – Initial screen: elevated immunoreactive trypsinogen (IRT) – Secondary screen: Repeat IRT ~2 weeks later – Avoids dealing with genetic data • IRT/DNA – Initial screen: elevated IRT – Secondary screen: limited genotyping – Avoids need to obtain follow-up blood

Approaches Vary • IRT/IRT – Maryland • IRT/IRT (conditional) – Virginia • IRT/∆F 508 – DC – (Maryland too)

IRT/IRT Negative Measure IRT Elevated Positive 2 elevated IRT

IRT/IRT (Conditional) Negative Measure IRT Elevated Negative Measure IRT Positive 2 elevated IRT

IRT/DNA Negative Measure IRT Elevated Negative Analyze for CFTR Mutations Positive 1 or 2 mutations Very elevated IRT

National Capital Area Military Newborn Screen • Contract with Pediatrix • Uses INNOGENETICS CFTR Assay • Hybrid of the two approaches (to ensure that they meet Maryland criteria) – 1 st IRT/∆F 508 – if one ∆F 508 mutation is identified, then extended panel is performed – 2 nd IRT – if second IRT is elevated, then extended mutation panel is performed

Pediatrix – 1 st Sample Negative Measure IRT Elevated Analyze for ΔF 508 0 1 Positive 2 Perform extended mutation panel

Pediatrix – 2 nd Sample Negative Measure IRT Elevated – 2 nd sample Analyze for extended mutation panel Positive

Now What? Remember Newborn Screening is a Screening Test !!

“Positive” CF Newborn Screen • False positive rate 70% • False negative rate 5. 4% • Children with Meconium Ileus have LOW IRT values – False negative rate 8. 2% • IRT values are elevated in premature infants Colorado 1, 153, 339 births (2 elevated IRT)

Diagnosis • Sweat Chloride • CFTR mutation analysis

Sweat testing • Pilocarpine Iontophoresis • Two Collection Methods – Gauze (Gibson-Cooke) – Microbore tubing (Macroduct®) • Should not be performed in the first 48 hours of life • Must measure chloride content (not conductivity)

Sweat Testing 1338 infants in Massachusetts Parad et al. J. Pediatr (2005) 147: S 69 -S 72

Sweat Chloride Results Normal <40 meq/L Borderline 40 -60 meq/L Abnormal (CF) >60 meq/L

Sweat Chloride in Infants Parad et al. J. Pediatr (2005) 147: S 69 -S 72

Diagnosis in Infants Normal <30 meq/L Borderline 30 -60 meq/L Abnormal (CF) >60 meq/L

1526 CFTR Mutations www. genet. sickkids. on. ca/cftr as of 9/1/2006

Detection of Cystic Fibrosis by Mutation Analysis Ethnic Group Detection Rate Mutations tested 25 97 Caucasian African American Hispanic Ashkenazi Jewish 90% 69% 57% 93% 81% 72% 97% unknown Other

CF Diagnosis is Confirmed • Refer to a CF Specialist • Multidisciplinary team approach – – – Pulmonologist Nutritionist Physical Therapist Social Worker Other specialists – GI, Endocrinology

Summary • Early intervention has the potential to decrease morbidity and improve survival • Newborn screening can identify MOST children with cystic fibrosis • Children with a negative newborn screen can still have cystic fibrosis – Meconium Ileus

Summary • Positive newborn screens must be followed up with a sweat test • Children with elevated (or borderline) sweat tests should be referred to a CF specialist