Pediatrics Grand Rounds 21 February 2014 University of Texas Health Science Center at San Antonio, Texas 1 Hemoglobinopathies (everything you wanted to know but were afraid to ask) (everything you wanted to know but were afraid to ask) Melissa Frei-Jones, MD MSCI Pediatric Grand Rounds February 21, 2014 Disclosure • I have no relationships with commercial companies to disclose. • I will be discussing off-label use of medications in children. – FDA - “Safety and effectiveness of hydroxyurea in children has not been established.” Learning Objectives • Plan the evaluation and counseling of patients with abnormal hemoglobinopathy testing on newborn screen. • Recognize the clinical and laboratory • Recognize the clinical and laboratory findings associated with quantitative hemoglobinopathies. • Integrate changes in sickle cell practice guidelines into primary and specialty care. Screening for Hemoglobinopthies • The test: – Thin layer isoelectric focusing (IEF) and high performance liquid chromatography (HPLC) – Approach 100% sensitivity and specificity • The results: – 76 possible results – 31 represent actual disease • DNA confirmatory testing – 45 represent trait or carrier status Screening for Hemoglobinopthies • The benefit: – Identify children with a disease that benefits from early detection • SCD to start prophylactic penicillin by 2 months of age to prevent pneumococcal infection • Thalassemia Major to start blood transfusion • The harm: – Incidental detection of trait/carrier status and hemoglobin disorders of questionable clinical significance – Parental anxiety and un-necessary testing in infants Interpreting Reports RESULT NOTE WHAT IT MEANS? Recommend consultation with pediatric hematologist. Call and discuss timing of repeat testing and refer if abnormal to hematologist. Consult with pediatric hematologist. Refer for counseling and visit by 6-12 months of age. Refer to pediatric hematologist. Hematology should see patient by 2 months of age. Notify family of test results. Provider discretion. Referral not necessary.
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Pediatrics Grand Rounds21 February 2014
University of Texas Health Science Center at San Antonio, Texas
1
Hemoglobinopathies
(everything you wanted to know but were afraid to ask)(everything you wanted to know but were afraid to ask)
Melissa Frei-Jones, MD MSCI
Pediatric Grand Rounds
February 21, 2014
Disclosure
• I have no relationships with commercial companies to disclose.
• I will be discussing off-label use of medications in children.– FDA - “Safety and effectiveness of hydroxyurea
in children has not been established.”
Learning Objectives
• Plan the evaluation and counseling of patients with abnormal hemoglobinopathy testing on newborn screen.
• Recognize the clinical and laboratory• Recognize the clinical and laboratory findings associated with quantitative hemoglobinopathies.
• Integrate changes in sickle cell practice guidelines into primary and specialty care.
Screening for Hemoglobinopthies• The test:
– Thin layer isoelectric focusing (IEF) and high performance liquid chromatography (HPLC)
– Approach 100% sensitivity and specificity
• The results:– 76 possible results
– 31 represent actual disease• DNA confirmatory testing
– 45 represent trait or carrier status
Screening for Hemoglobinopthies• The benefit:
– Identify children with a disease that benefits from early detection
• SCD to start prophylactic penicillin by 2 months of age to prevent pneumococcal infection
• Thalassemia Major to start blood transfusion
• The harm:– Incidental detection of trait/carrier status and
hemoglobin disorders of questionable clinical significance
– Parental anxiety and un-necessary testing in infants
Interpreting Reports
RESULT NOTE WHAT IT MEANS?
Recommend consultation with pediatric hematologist.
Call and discuss timing of repeat testing and refer if abnormal to hematologist.
Consult with pediatric hematologist. Refer for counseling and visit by 6-12 months of age.
Refer to pediatric hematologist. Hematology should see patient by 2 months of age.
Notify family of test results. Provider discretion. Referral not necessary.
Pediatrics Grand Rounds21 February 2014
University of Texas Health Science Center at San Antonio, Texas
2
So when should I repeat testing?
• In disease –– Specialist may repeat testing at 6-12 mo
– CBC, retic and Hemoglobin Analysis
• In common traits (S, C, D, Alpha Thal) -( p )– Not required
• Uncommon traits (Other) –– Repeat at 6-12 months when Hb F levels fall to see if
abnormal hemoglobin persists • May represent prenatal hemoglobin
– CBC, Hemoglobin Analysis, Pulse Oximetry
What is missing on NBS?
• Beta Thalassemia Trait
• Beta Thalassemia Intermedia
• Why?• Why?– Detected by development of microcytosis after
Hb F falls (Hb F = increased MCV).
– Elevated Hb A2 (>3%)• Won’t be elevated in newborn period due to Hb F
The Name Game
SCREEN RESULT
• F A
• F A BART’S
• F A S BART’S
DIAGNOSIS
• NORMAL
• ALPHA THAL TRAIT
• S TRAIT AND ALPHA THAL
• F S
• F ONLY
• F A OTHER
• F A C
• F A S
TRAIT
• SICKLE CELL ANEMIA
• BETA THALASSEMIA MAJOR
• NON-C, D, E, G, S TRAIT
• C TRAIT
• S TRAIT
What is Hemoglobin Bart’s?• Decreased alpha globin production results in excess
• Iron Overload– Liver, cardiac and endocrine sequelae
– Challenges of chelation
• Transition to adult care……
Pediatrics Grand Rounds21 February 2014
University of Texas Health Science Center at San Antonio, Texas
8
Stopping Transfusions
• STOP II Trial– Discontinuation of prophylactic transfusion
• Reappearance of abnormal TCDpp
• Increase risk of overt stroke
• Increase risk of silent stroke
• Recurrent stroke despite transfusion– 2.2 per 100 pt/years
Hydroxyurea in Stroke
SWITCH Trial
• Phase III Multi-Center non-inferiority RCT
• Chronic transfusion/chelation versus
TWITCH Trial
• Hydroxyurea versus chronic transfusion for abnormal TCD– Pts on chronic transfusiontransfusion/chelation versus
convert to hydroxyurea/phlebotomy
• Primary endpoint – Stroke and iron overload
• DSB– Trial halted early
– 7 strokes in HU/phlebotomy arm/0 in transfusion/chelation with equivocal liver iron
Pts on chronic transfusion randomized to change to hydroxyurea
– Overlap between transfusions and hydroxyurea
• Ongoing
Barriers to Hydroxyurea Use
• Adherence to medication– Monthly MD visits
• Cost of weekly to monthly CBCy y
– Taking a medication daily
• Delay in onset of effect (3 months)– Underdosing contributes
• Patient/Provider fears
• Lack of provider consensus
WARNING Treatment of patients with DROXIA (hydroxyurea capsules, USP) may be complicated by severe, sometimes life-threatening, adverse effects. DROXIA should be administered under the supervision of a physician experienced in the use of this medication for the treatment of sickle cell anemia. Hydroxyurea is mutagenic and clastogenic, and causes cellular transformation to a tumorigenic phenotype. Hydroxyurea is thus unequivocally genotoxic and a presumed transspecies carcinogen which implies a carcinogenic risk to humans In patients receiving long-termimplies a carcinogenic risk to humans. In patients receiving long term hydroxyurea whether this leukemogenic effect is secondary to hydroxyurea or is associated for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemias have been reported. It is unknown with the patients’ underlying disease. The physician and patient must very carefully consider the potential benefits of DROXIA relative to
the undefined risk of developing secondary malignancies.
Pulmonary Hypertension
• 2004, Pulm HTN in 1/3 of adults with SCD– Pts with TR jet > 2.5 m/s vs
with < 2.5 m/s
• Screening and Treatment – Echo and Right heart cath
for symptomatic patients
– No proven treatment
– RR 10.1 of sudden death, 95% CI 2.2-47, p <0.001
• Must confirm with right heart cath – 2012, 40% abnormal by
echo but only 10% with Pulm HTN on cath
currently available
• Walk-PHASST Trial– Sildenafil for Pulm
HTN
– Ended early due to increased frequency pain in treatment arm
Sickle Cell Pain
• Acute pain– Most common
manifestation of SCD• Adults reported 54% of
days in pain
• Symptomatic care– Opioids
– Nsaids
– Alternative methodsdays in pain
– Affects entire family• 25% parents miss work
• 54% miss 2 or more days of school
• Chronic pain– Increasing recognition
• Heat
• Acupuncture
• PT
• Biofeedback
• Hydroxyurea
• Transfusions
Pediatrics Grand Rounds21 February 2014
University of Texas Health Science Center at San Antonio, Texas
9
Transition from Pediatric to Adult Care
• Before 1970, 50% of children with SCD live to adulthood
• Now > 90% survive to
• Barriers– Financial
• Loss of medicaid
L k f d l i kl• Now > 90% survive to adulthood
• 32% unsuccessful in transition– Success = establish care
with adult provider by attending appointments/not using ED