SICKLE CELL DISEASE/DIABETES
From the 36th Annual Pediatric Trends, presented by Johns Hopkins Children’s Center and Johns Hopkins University
School of Medicine, Continuing Medical Education, Baltimore, MD
Educational Objectives
| The goal of this program is to improve the medical care of children with sickle cell disease and children with type 1
diabetes mellitus. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Describe the possible genotypic representations of sickle cell disease.
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| 2. Identify patients with sickle cell disease who are at high risk for severe disease.
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| 3. Describe effective therapies for managing sickle cell disease in children.
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| 4. Choose appropriate medication and delivery devices for patients with type 1 diabetes.
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| 5. Evaluate the efficacy of glucose monitoring devices.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the faculty and the planning committee reported nothing to disclose.
Acknowledgments
Drs. Strouse and Cooke were recorded at the 36th Annual Pediatric Trends, presented April 7-11, 2007, in Baltimore,
MD, by Johns Hopkins Children’s Center, and Johns Hopkins University School of Medicine, Continuing Medical
Education, Baltimore. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the
production of this program.
SICKLE CELL DISEASE IN THE NEW MILLENNIUM —John J. Strouse, MD, Assistant Professor of Pediatrics, Johns
Hopkins University School of Medicine, Baltimore
| Introduction: survival in sickle cell disease (SCD) accelerated since 1970 (almost every child with SCD survives to
adulthood)
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| Newborn screening: SCD most commonly identified condition (prevalence 1 in 1000 births (in blacks, 1 in 346 births
[data from California]); other populations at risk—Hispanic, Arabic, Turkish, Indian
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| Pathogenesis of SCD: point mutation causes cells to become deoxygenated; hemoglobin polymers cause deoxygenated
cell to deform (ie, sickle); sickle cells have decreased survival and adhere to blood vessels, causing blockages that lead to
complications of SCD, including frequent pain
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| Genotypes of SCD: sickle cell anemia (homozygous hemoglobin S; HbSS)—most common (affects two-thirds of patients
with SCD at birth); sickle C disease (hemoglobin SC; HbSC)—next most common (accounts for 20%-30%);
milder disease; with exception of retinopathy and avascular necrosis, fewer complications of SCD; sickle- β null thalassemia
(HbS β 0) —similar to HbSS disease in presentation, severity, and degree of anemia; fewer strokes; sickle- β plus
thalassemia (HbS β + )—together with HbS β0 , accounts for 4% to 5% of patients with SCD in United States
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| SCD and malaria: people with sickle cell trait have mild protection against malaria; malaria powerful selective force
(helps explain heightened incidence of SCD in Africa)
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| Definitions: death or stroke; >2 or 3 hospitalizations/yr for pain; frequent episodes of acute chest syndrome (ACS); severity
influenced by improvements in care—prevention of infection through vaccinations and penicillin prophylaxis; empiric
treatment and supportive care (better critical care and transfusion therapy)
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| Signs and symptoms of ACS: pulmonary infiltrate and—fever; chest pain; increased work of breathing; etiology
diverse—pulmonary infection; sickling in lungs; fat or bone emboli after sickling in bone
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| Predictors of severe disease
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| Older criteria: in first year of life, dactylitis; in second year of life, Hb <7 g/dL or white blood cell [WBC] count
>20,000/µL
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| Newer criteria: WBC count >20,000/µL still independent predictor of severity; network models—history of blood
transfusion, increased bilirubin, reticulocytes, WBCs, and mean corpuscular volume (MCV); male sex; Sebastiani et
al, 2005—prognostic modeling of stroke; asthma—prevalence in patients with SCD ≈20% (similar to that in blacks
without SCD); associated with increased admissions for pain, ACS, and transfusions
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| Prevention and management of infection in patients with SCD
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| Current standard: penicillin prophylaxis from birth to 5 or 6 yr of age reduces number of pneumococcal infections;
immunizations—pneumococcal vaccine polyvalent (Pneumovax) at 2 and 5 yr of age, then every 6 yr as booster, or
pneumococcal 7-valent conjugate vaccine (Prevnar); influenza vaccination; evaluate fever ≥101.5°F (38.5°C)—
administer empiric parenteral antibiotics (eg, ceftriaxone); if age <3 yr, hospitalize for observation while awaiting results
of cultures and other studies
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| Epidemiology: in post-Prevnar era, rate of invasive pneumococcal disease in children <2 yr of age 10% of previous levels
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| Infection and ACS: infectious etiology identified in ≈33% of younger children with ACS (20%-25% of older children);
bacterial infection—Chlamydia pneumoniae and Mycoplasma most common pathogens; if pulmonary infiltrate
present, include coverage for atypical pathogens; consider macrolide antibiotic (eg, azithromycin or clarithromycin);
viruses—in younger children, many viral infections implicated (respiratory syncytial virus [RSV; most common];
influenza); other bacterial infections—pneumococcus; Haemophilus influenzae; Legionella
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| Pathogens causing bloodstream infections: Staphylococcus aureus common; Staphylococcus epidermidis; gram-negative
bacilli (Salmonella may be associated with osteomyelitis; Escherichia coli); other factors—urinary tract infection due
to sickling in kidney; pneumonia and ACS
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| Central nervous system (CNS) complications
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| Stroke: occurs by 19 yr of age in ≈10% of patients with HbSS disease; screening with transcranial Doppler (TCD) ultrasonography
(US) used to identify patients at high risk (transfusion every 4 wk reduces risk to 1%/yr; 30-mo therapy inadequate);
TCD US shows blood flow to brain (procedure painless with no known side effects); arterial blood flow
velocity >200 cm/sec used to decide whether transfusion indicated; causal pathway for stroke—patients with SCD
typically develop stenoses around bifurcation, endothelial hyperplasia, and narrowing of blood vessels
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| Silent cerebral infarct: frequent complication of SCD; defined as ischemic changes on MRI without history or physical
examination consistent with stroke; affects 16% to 35% of children with sickle cell anemia; lesions associated with increased
risk for—cognitive impairment, school failure, and overt stroke
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| Pulmonary hypertension (PHTN)
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| Overview: mild PHTN defined as tricuspid regurgitant jet velocity [TRJV] ≥2.5 m/sec; in moderate PHTN, TRJV ≥3 m/
sec; in study, mortality 40% over 40 mo; associated with increased intravascular hemolysis and decreased bioavailability
of nitric oxide
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| Pediatric PHTN
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| PHTN common in children: 30% have TRJV ≥2.5 m/sec (8%, ≥3 m/sec); unclear whether noninvasive screening correlates
with results of right heart catheterization in children
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| Should we screen children? pros—significant adult mortality; PHTN may be reversible; interventions available to decrease
hemolysis; cons—no longitudinal data; lack of validation; no proven treatment
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Management of SCD
| Transfusion: treatment—transfusion first-line treatment for stroke or severe episode of ACS; prevention—
complications from anesthesia with preoperative transfusion; primary and secondary prevention of stroke; advances
since 2000—deferasirox (Exjade; oral iron chelator); nucleic acid testing (NAT) for HIV-1 and -2, hepatitis C virus,
and West Nile virus (identifying viral infection in blood helps decrease window of susceptibility in which patient has
not initiated immune response)
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| Overview: ribonucleic reductase inhibitor; increases fetal and total hemoglobin, and MCV; lowers WBC count and number
of reticulocytes; decreases hemolysis; approved for treatment of adults with sickle cell anemia and frequent severe
pain
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| National Institutes of Health (NIH) Consensus Development Conference, 2008
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| Efficacy in adults: increases fetal and total hemoglobin; reduces painful episodes, hospitalizations, ACS, and transfusions;
efficacy in children—increases fetal and total hemoglobin; reduces painful episodes and admissions; may decrease
CNS complications
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| Adverse effects: short term—decrease in WBCs, platelets, and reticulocytes; rash and hyperpigmentation of skin and
nails (rate ≈10%); rarely, nausea and serum alanine aminotransferase (ALT) elevation; long term—no evidence of
increased risk for leukemia in SCD; concern about reproductive toxicity based on animal data (human data limited;
sexually active patients with SCD should use reliable contraception)
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| Barriers to treatment: fears about cancer, birth defects, and infertility; concerns that hydroxyurea therapy experimental
in children; lack of knowledge about hydroxyurea; lack of adherence to treatment regimen; need for frequent monitoring;
limited number of physicians with expertise; limited access to care
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| Pediatric matched allogeneic transplant: hematopoietic stem cell transplantation reasonable option for severe
SCD, as long as donor HLA-matched sibling; almost 200 transplants published (overall survival, 95%; rate of rejection,
10%); rate of acute graft-vs-host disease (GVHD) 20% (chronic GVHD, 13%); use of cord blood increasing; experimental
approaches—alternative donors; reduced intensity conditioning
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| Gene therapy: cure for SCD effective in mouse model; mutation corrected by targeting specific gene
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| Take-home points: prevention strategies—routine care (immunizations, penicillin, screening); comanagement with pediatric
hematologist; ophthalmologic examinations in children ≥10 yr of age; choice of screening depends on genotype—
for HbSS or HbS β0 disease, TCD; for PHTN, echocardiography; hydroxyurea—underutilized in adolescents
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| WHAT’S NEW IN TYPE I DIABETES MELLITUS ?—David W. Cooke, MD, Associate Professor of Pediatrics, Division
of Pediatric Endocrinology, and Director, Pediatric Endocrine Fellowship Training Program, Johns Hopkins University
School of Medicine, Baltimore
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| Basal-bolus insulin regimens: 1) multiple daily injections (MDI); 2) continuous subcutaneous insulin infusion (CSII;
insulin pump)
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| MDI therapy: basal dose given as long-acting insulin—bolus dose given as rapid-acting insulin at mealtime; minimum
4 injections/day—eg, glargine once daily, plus boluses at breakfast, lunch, and dinner; additional insulin doses—may be
given as “correction doses” for high blood glucose levels or for snacks; caveat—limit to number of injections child with
diabetes can reasonably be expected to take
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| Specific products: rapid-acting insulin—insulin aspart (NovoLog), insulin glulisine (Apidra), and insulin lispro (Humalog)
equivalent (no physiologic difference); basal insulin—insulin detimer (Levemir; bid dosing recommended [some
use once-daily dosing]); insulin glargine (Lantus; better profile for once-daily dosing)
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| Continuous subcutaneous insulin infusion (insulin pump therapy): use rapid-acting insulin—basal rate can
vary throughout day (accommodate dawn phenomenon; decrease basal rate with exercise); bolus—patient or parent directs
pump to give bolus for meals and snacks, or to correct high blood glucose levels; lack of requirement for injection
may increase frequency of bolus doses (too-frequent doses can result in “insulin stacking,” increasing risk for hypoglycemia;
change insulin infusion set—every 2 to 3 days
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| Advantages: for very small children, may facilitate delivery of small insulin doses (basal rates as low as 0.25 U/hr; bolus
doses as low as 0.05 U); fewer needlesticks/day; ability to provide different basal rates throughout day; may decrease
rate of severe hypoglycemia (few reports of increased hypoglycemia)
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| Disadvantages: increased risk for diabetic ketoacidosis (DKA)—more theoretic than practical (seen in some studies, not
others); with insulin pump, no depot of insulin in patient (if pump failure occurs, insulin levels fall rapidly and DKA
can result within few hours; problem avoidable by educating patients about risk and need to respond quickly to rising
blood glucose levels); need to wear medical device—unacceptable to some patients (youngest patients may disconnect
tubing inadvertently); increased frequency of hypoglycemia—seen in some studies (others show decreased frequency);
risk that patient will allow pump to manage diabetes—patient must still check blood glucose levels and remember to
administer meal boluses
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| Does use of insulin pump improve outcomes?
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| Main study outcomes: risk for DKA and hypoglycemia
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| Hemoglobin (Hb) A1C as marker for glucose control: in adults—studies suggest use of pump decreases Hb A1C 0.5% to
1.2%; in children—no definitive studies (most observational; most show modest lowering of Hb A1C or no change)
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| Patients with poor glycemic control: Iafusco et al—for patients with good control, switch to pump made little difference
(those with Hb A1C of 9.3% had larger decrease); DiMeglio et al—similar results (patients with worse control had
more significant improvement); Nimri et al, 2007—again, as Hb A1C increases, improvement with pump use increases;
Wills et al, 2003—initial Hb A1C had no correlation with improvement seen with pump; study findings mixed
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| Reducing microvascular risk (Diabetes Control and Complications Trial [DCCT]): goal not to decrease
Hb A1C , but to decrease microvascular complications; if Hb A1C decreased from 8.9 to 7.0, risk for retinopathy decreased
76% (if Hb A1C decreased from 8.5 to 8.0, risk decreased 20%)
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| Advantages of combined therapy (untethered regimen): allows patients to disconnect from pump for longer
periods (ie, >1 hr); protects against DKA due to pump failure, tubing changes or bubbles in tubing, insulin leakage, and
depleted batteries; combined therapy option as daily regimen or for special events in which pump use impractical
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| Real-time continuous glucose monitoring systems (CGMS)
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| Specific products: Guardian, approved by Food and Drug Administration (FDA) for children ≥7 yr of age; DexCom STS,
approved only for adults; FreeStyle Navigator, recently approved for use in patients ≥18 yr of age
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| Benefit: these systems supplement (but do not replace) information from fingerstick glucose checks (they should not be
relied on for treatment decisions); accuracy +/- 20%; biggest advantage that they provide information on trends; in
adults (Garg et al, 2006)—less hypoglycemia and hyperglycemia, and greater percentage of time within target range;
in children (Diabetes Research in Children Network Study Group, 2007)—participants tolerated monitors well (monitors
on 134 hr/wk for 13 wk)
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| CGMS issues: cost about $10/day; many false alarms; possible skin irritation due to adhesive; finding adequate sites may
be difficult in small children and patients using pumps; ability to track trends (ie, whether blood glucose level falling or
rising) very helpful
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| Introduction: neonatal diabetes presents within first 6 mo of life; can be transient or permanent; several loci of genetic
mutation identified
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| Mutations in Kir 6.2 and SUR1 genes: components of potassium channel involved in glucose sensing in β cells of pancreas
(closure of channel stimulates insulin secretion); mutations do not allow channel to close normally, blocking insulin
secretion; homozygous activating mutations result in neonatal diabetes; Kir 6.2 also expressed in muscle and
neurons (patients may also have neurologic deficits, eg, developmental delay, muscle weakness, epilepsy)
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| Treatment: because sulfonylurea receptor involved, patients can be treated with sulfonylureas (glycemic control often
improved remarkably with sulfonylurea, compared to insulin treatment); children diagnosed with diabetes at <6 mo
of age (or perhaps <1 yr) should be investigated for presence of KCNJ11 gene mutation (most common) or ABCC8
(gene for sulfonylurea receptor); mutation in glucose kinase gene leads to maturity-onset diabetes of youth (mild
form of type 1 diabetes that does not require insulin); if both parents glucose intolerant, consider evaluation of glucose
kinase gene
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Suggested Reading
Bernaudin F et al: Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood
110:2749, 2007; Boyd JH: Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia.
Bolld 108:2923, 2006; Diabetes Research in Children Network (DirecNet) Study Group et al: Continuous
glucose monitoring in children with type 1 diabetes. J Pediatr 151:388, 2007; Gladwin MT et al: Pulmonary hypertension
as a risk factor for death in patients with sickle cell disease. N Engl J Med 350:886, 2004; Iafusco D et al: The egg or
the chicken? Should good compliance to multi-injection insulin therapy be a criterion for insulin pump therapy, or does insulin
pump therapy improve compliance. J Pediatr 148:421, 2006; Miller ST et al: Silent infarction as a risk factor for overt
stroke in children with sickle cell anemia: a report from the Cooperative Study of Sickle Cell Disease. J Pediatr 139:385,
2001; Nimri R et al: Insulin pump therapy in youth with type 1 diabetes: a retrospective paired study. Pediatrics
117:2126, 2006; Sebastiani P et al: Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat
Genet 37:435, 2005; Vichinsky EP et al: Causes and outcomes of the acute chest syndrome in sickle cell disease. National
Acute Chest Syndrome Study Group. N Engl J Med 342:1855, 2000; Wang WC et al: A two-year pilot trial of hydroxyurea
in very young children with sickle-cell anemia. J Pediatr 139:790, 2001; Willi SM et al: Benefits of continuous
subcutaneous insulin infusion in children with type 1 diabetes. J Pediatr 143:796, 2003.
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