Newborn Screening: Sickle Cell Disease Peter Lane, MD Screening: Sickle Cell Disease ... Individuals at risk ... Newborn Screening for SCD in GA HPLC and isoelectric focusing

Newborn Screening: Sickle Cell Disease

Peter Lane, MD

At the completion of this session, the participant will be able to:

Review the genetics, pathophysiology, and clinical manifestations of SCD

Understand the organization of and access to newborn screening follow-

up services

Understand the incidence, demographics and mortality of SCD in Georgia

Appreciate challenges of transition to adult care for individuals with SCD

Dr. Lane has no significant financial relationships to disclose. He will not be discussing products which he had a

role in developing. He will include a discussion of Hydroxyurea which is not yet FDA approved for use in

children. His presentation will include patient care recommendations.

This CME activity is supported by an educational grant from the GA Department of Public Health

Peter A Lane, MD

Professor of PediatricsEmory University School of Medicine

Director, Sickle Cell Disease Program

Children’s Healthcare of Atlanta

SICKLE CELL DISEASE IN GEORGIA

From Newborn Screening to Transition

Dr. Lane has no significant financial relationships to disclose. He

will not be discussing products which he had a role in

developing.

He will include a discussion of Hydroxyurea which is not yet FDA

approved for use in children. His presentation will include

patient care recommendations.

Disclosure Information

SICKLE CELL DISEASE (SCD) IN GEORGIAObjectives

• Review the genetics, pathophysiology, and clinical manifestations of SCD

• Understand the organization of and access to newborn screening follow-up services

• Understand the incidence, demographics and mortality of SCD in Georgia

• Appreciate challenges of transition to adult care for individuals with SCD

Aflac Cancer and Blood Disorders Center

SICKLE CELL DISEASE IN GEORGIA

• Brief Overview of SCD

Pathophysiology

Clinical manifestations

Genetics and inheritance

• GA Newborn Screening and Follow-up Program

• Results of SCD surveillance in Georgia

• SCD mortality in Georgia

• Transition to adult care

• Management Guidelines and Resources for Providers



Point mutation in β-globin: β6 (Glu Val)

Most common hemoglobin variant worldwide

Sickle cell trait (AS)

• 7-8% Africans Americans• Hispanic, Mediterranean, Middle East, Caribbean, India,

Central & South America

≥ 100,000 persons with SCD in US

Deoxy-Hb S polymerizes

• Damages RBC hemolysis• Vaso-occlusion and tissue injury

Sickle Hemoglobin (Hb S)


SICKLE CELL DISEASE

Clinical Manifestations of Hemolysis

• Chronic anemia

• Jaundice

• Cholelithiasis

• Aplastic crisis

• Decreased energy / exercise intolerance

• Growth and pubertal delay


Sickling and Vaso-occlusion

Hemolysis Vasoocclusion

SICKLE CELL DISEASE

Acute Events• Pain• Splenic sequestration• Infection• Acute chest syndrome• Stroke• Priapism

Chronic Organ Damage• Splenic dysfunction• Chronic pain • Lung disease• Neuro-cognitive • Pulm hypertension• Nephropathy

Treatment Complications• Medication toxicity • Iron overload• RBC alloimmunization• Other iatrogenic

Psychosocial Complications• Absence from school & work• ↓ Academic achievement • ↓ Readiness for transition • Stress, depression, ↓ self esteem

AAC

Complex Progressive Chronic

Vasculopathy

↓Quality of LifeMorbidityEarly DeathHigh Cost

Sickle Cell Anemia: Autosomal Recessive Inheritance

SICKLE CELL DISEASE

Vasoocclusion

++++

++ / ++++

-

+ / ++0

Genotype *

Hb SS

Hb SC

S β thalassemia

S β thalassemia

Approx % of

U.S. Patients

65

25

7

2 ++++

Hemolysis

++++

+

+

+++

*Each genotype characterized by largely

unpredictable and widely variable phenotype

SD, SO, SE, SLepore 1 Varies Varies

SICKLE CELL DISEASE

Family testing for Carriers *

Individuals at risk• Sickle cell trait (AS)

• Hemoglobin C trait (AC)

• β thalassemia

• Other hemoglobin variants

Laboratory testing • Hemoglobin electrophoresis, HPLC

• CBC / MCV

• Quantitation of A2 & F if MCV low or

low normal

*Provided by Sickle Cell Foundation of

Georgia at reduced or no cost Aflac Cancer and Blood Disorders Center

S

Sickledex(Hemoglobin

solubility

test)

NEWBORN SCREENING (NBS) FOR SCD IN GEORGIA

• 1980: Targeted screening of cord blood

• 1998: Universal screening of NBS dried blood spot specimens

• ~130,000 births per year

• ~130 infants with SCD born annually (SS, SC, Sβ+thal, Sβᴼthal, other SCD genotypes)

• SCD most prevalent disorder identified by NBS in GA (1:1,000)


Genotype Approx %

of U.S.

Patients

Newborn

Screening

Results

Hb SS 65 FS

SC 25 FSC

S β+-

Thalassemia8 FSA or FS

S βo-

Thalassemia2 FS

Newborn Screening for SCD in GA

HPLC and isoelectric focusing


Genotype % of

U.S.

Patien

ts

Newbo

rn

Screeni

ng

Results

SS 65 FS

SC 25 FSC

S β+-

Thalasse

mia

8FSA or

FS

S βo-

Newborn Screening for SCD in GA

HPLC and isoelectric focusing


NEWBORN SCREENING (NBS) in GAHemoglobinopathy Follow-up Program

• Clinically significant disease (FS, FSC, FSA FC, FE)

NBS lab faxes results to NBS F/U coordinators (CHOA/GRU)

Confirmatory testing (Hgb electrophoresis/HPLC)

Parental education

Penicillin prophylaxis (SCD)

Referral for comprehensive specialty care

Complete follow-up activities within 2 months of age

• Heterozygous carriers (FAS, FAC, FAE, etc)

Results sent to Sickle Cell Foundation of Georgia

Family testing, education, and counseling


Aflac Cancer and Blood Disorders Center | Emory University

Newborn Screening (NBS) in Georgia:~130 infants with SCD /yr

•

17

AugustaAugustaAugustaAugustaAugustaAugustaAugustaAugustaAugusta

MaconMaconMaconMaconMaconMaconMaconMaconMaconColumbusColumbusColumbusColumbusColumbusColumbusColumbusColumbusColumbus

SavannahSavannahSavannahSavannahSavannahSavannahSavannahSavannahSavannah

NBS lab faxes results to F/U Programs• CHOA for metro Atlanta (~85/yr)• GRU for non-metro Atlanta (~65/yr)

F/U Coordinators at CHOA and GRU• Contact PCP within 24-72 hr (~60%)• Contacts families directly (~40%)• Coordinates F/U activities with PCP• Confirmatory testing • Initiation of PCN prophylaxis• Referral to Comprehensive SCD

clinics• Referral for family testing• Documentation in SENDSS

Sickle Cell Disease ProgramChildren’s Healthcare of Atlanta

• Largest in US (1,800 active patients annually)

• Comprehensive clinics, ED and inpatient services

Egleston

Scottish Rite

Hughes Spalding

• Multidisciplinary SCD teams on all 3 campuses

Hematologists, nurse practitioners, nurses, social workers, psychologists, child life specialists, chaplains

• NBS Follow-up Program

Confirmatory testing in CHOA lab

Initial outpatient consultation

Subsequent coordination of care with PCPAflac Cancer and Blood Disorders Center

NEWBORN SCREENING FOR SCDScreening System Failures

• Blood transfusion prior to screening

• Extreme prematurity

• Sample never drawn or lost in transit to lab

• Inadequate sample

• Mislabeled specimen

• Laboratory or clinical error

• Inability to locate infant

• Inappropriate confirmatory testing or interpretation

• Parental denial

Aflac Cancer and Blood Disorders Center Aflac Cancer and Blood Disorders Center

NEONATAL SCREENING RESULTS

“No news is no news!”

Aflac Cancer and Blood Disorders Center Aflac Cancer and Blood Disorders Center | Emory University

Public Health Surveillance for SCD in Georgia

NIH/CDC RuSH Grant: (2010-2012)

• One of 7 states funded to conduct surveillance for SCD and thalassemia

CDC PHRESH Grant: (2012-2014)

• Only state (of 7) funded for continued SCD surveillance

Georgia CDC Transfusion Complications Grant: (2014-2019)

• Only state funded to characterize and reduce complications of blood transfusions in SCD & thalassemia

CDC Foundation Grant (2016)

• Extend SCD surveillance to include 2004-2014


Surveillance for SCD in Georgia 2004-2008

Results of CDC-funded RuSH Project

24

Surveillance for SCD in Georgia 2004-2008Cases by County and SCD Clinics

Comprehensive SCD centers (CHOA, Grady, GRU)Public Health Outreach sickle cell clinics

Number of residents with sickle cell disease* by county, 04-08

Dublin – Pediatric Athens – Pediatric Macon – AdultSavannah – Adult

Waycross – Pediatric and adultValdosta – Pediatric and adult Albany – Pediatric and adult

SCD residents per 100,000

*thalassemia excluded

SCD births 2004-2008

0

1 - 10

11 - 20

21 - 100

101 +

Hospital Encounters by Age for SCD*

* For individuals who had at least one ER or in-patient encounter in 2004-2008Aflac Cancer and Blood Disorders Center

Data from Georgia Registry and Surveillance for Hemoglobinopathies (RuSH)

Care Providers for SCD Patients in GA

Provider SpecialtyOutpatient

VisitsPercentage of

Visits

Internal Medicine 52,890 19%

Family Practice/General Practice 48,161 17%

Pediatrics 40,554 14%

Hematology 31,512 11%

Emergency Medicine 16,976 6%

Population: Medicaid all-cause outpatient visits 2004-2008 for confirmed and probable cases of SCD

Aflac Cancer and Blood Disorders CenterData from Georgia Registry and Surveillance for Hemoglobinopathies (RuSH)

Age at Date of Death in SCD

RuSH Dx Level Observations N Mean Median Mode

Confirmed 268 136 37.55 38 50

Probable 280 208 44.99 44 55

Total 548 344 42.05 41 50

Aflac Cancer and Blood Disorders CenterData from Georgia Registry and Surveillance for Hemoglobinopathies (RuSH)

SCD not listed on death certificate in 55% of cases!

SCD Mortality in GeorgiaCDC-RuSH Surveillance Project (7,299 patients)*

SCD not listed on death certificate in 55% of cases!

BARRIERS AND CHALLENGES TO TRANSITION TO ADULT CARE

• Parents enablement and fostering of dependency

• Pediatric providers enablement and fostering dependency

• Over dependence on pediatric providers

• Adolescents lack of SCD specific knowledge

• Neurocognitive and/or developmental delays

• Low self-esteem and self reliance

• Inadequate academic and vocational skills

• Lack of health insurance

• Lack of adult providers with interest and expertise in SCD

• Ineffective pediatric / adult provider communication


Clinical Report on Health Care Transition AAP/AAFP/ACP 2011*

Targets all youth, beginning at age 12

Algorithmic structure with

• Branching for youth with special health care needs

• Application to primary and specialty practices

• Extends through transfer of care to adult medical home

* Pediatr 2011: 128; 182

DeBaun, Telfair: Transition and Sickle Cell Disease. Pediatr 2012: 130; 1

www. gottransition.org

Age 12 – Youth and family aware of transition policy

Age 14 – Health care transition planning initiated

Age 16 – Preparation of youth and parents for adult approach to care and discussion of preferences and timing for transfer to adult health care

Age 18 – Transition to adult approach to care

Age 18-22 – Transfer of care to adult medical home and specialists with transfer package


NIH: Evidence-Based Management of

Sickle Cell Disease 2014

Objective:

• To expand the number of health

professionals able and willing to provide

care for persons with SCD

Target audience:

• PCPs, other health care professionals

Contents:

• Health Maintenance

• Management of Acute Complications

• Management of Chronic Complications

• Hydroxyurea Therapy

• Blood Transfusions

Yawn, et al, JAMA 2014: 321(10): 1033-1048

http://www.nhlbi.nih.gov/health-

pro/guidelines/sickle-cell-disease-guidelines


Red Blood Cells

HYDROXYUREA

Before Hydroxyurea On Hydroxyurea

MULTICENTER STUDY OF HYDROXYUREA IN SCD

Charache, et al., NEJM 1995; 332: 1317-1322

Event Hydroxyurea

(n=152) Placebo (n-147) P value

Pain events / year 2.5 4.6 .001

Hospitalizations / year for pain

1.0 2.5 .0027

Episodes of ACS 56 101 .003

Patients transfused 55 79 .002

Transfusion units 423 670 .003


HYDROXYUREA IN Hb SS and S β°thalassemia Established Efficacy

• Sustained hematologic efficacy (age >1 yr)

• Decreased pain (age >1 yr)

• Decreased ACS (age >1 yr)

• Decreased hospitalization (age >1 yr)

• Decreased acute transfusions (age > 1 yr)

• Improved quality-life in children and adults

• Reduced mortality in adults

• Uncertain but suspected reduction in chronic organ damage

34


NIH Treatment Recommendations Use of Hydroxyurea in Children with SCA*

• Educate all patients with SCA and their families about hydroxyurea

• In infants 9 months of age and older, children, and adolescents with SCA, offer treatment with hydroxyurea regardless of clinical severity to reduce SCD-related complications (e.g. pain, ACS, anemia)

35

* Not yet FDA approved for use in children


CHOA SCD Program

Increased Hydroxyurea (HU) Utilization*

36

* SS/ Sβ°-thalassemia not on chronic blood transfusions

Reduced utilization 2 years after vs. 2 years before

initiation of HU

Pain Encounters 36%

Acute Chest Syndrome 43%

ED Visits 43%

Hospitalizations 47%

Inpatient Days 50%

Blood transfusions 57%

* Quarmyne, et al: Am J Hematol 2016

HU may be more effective when started in patients <10 years of age

Effectiveness of Hydroxyurea (HU)*Reduced Utilization after Initiation of HU

37

SICKLE CELL DISEASE IN GEORGIASummary

Major health issue in children and adults across GA

• Multiple SCD genotypes with variable manifestations and severity

• Complex progressive chronic vasculopathy

• Life-threatening acute and chronic complications

• Significant morbidity and early mortality

Newborn F/U programs housed at CHOA and GRU (Augusta University)

• Prompt confirmatory testing, family education, specialty care, ongoing

partnership between SCD clinic and PCP

Major challenges with transition to adult care

• Inadequate number of adult providers with expertise in SCD

• Marked increase in ED and inpatient utilization and mortality after age 18

NIH Evidence-based Management Recommendations, including use of HU


SICKLE CELL DISEASE IN GEORGIAOther Resources for Providers

On-line:http://ghpc.gsu.edu/project/hemoglobin-disorders-data-coordinating-center/www.scifo.org

Phone Contacts:

Newborn Screening Follow-up Coordinators

• Greater Metro Atlanta 404 785-1087

• Outside Metro ATL 706 721-6251

Sickle Cell Foundation of Georgia 404 755-1461

Pediatric SCD Clinics

• CHOA at Hughes Spalding 404 785-7893

• CHOA at Egleston 404 785-1319

• CHOA at Scottish Rite 404 785-3519

• Augusta University 706 721-4929

Adult SCD Clinics

• Grady Hospital 404 616-5984

• Augusta University 706 721-2171Aflac Cancer and Blood Disorders Center

http://ghpc.gsu.edu/project/hemoglobin-disorders-data-coordinating-center/

http://www.scifo.org/

Documents

Newborn Screening: Sickle Cell Disease Peter Lane, MD Screening: Sickle Cell Disease ... Individuals at risk ... Newborn Screening for SCD in GA HPLC and isoelectric focusing