Doctor123.org

Sickle Cell Disease, Pediatric

Basics

Description

- Subsequent to diagnosis - SCD genotype - History of: - Surgery - Transfusion (red cell phenotype) - Hospitalizations (particularly ICU) - Pain (sites and usual therapy) - Stroke and/or transcranial Doppler (TCD) abnormalities - Acute chest syndrome

- Baseline hemoglobin and pulse oximetry - Current medication and therapy

- Diagnostic - All states have newborn screening. - F: thalassemia major - FA: normal hemoglobin - FAS: A > S: sickle cell trait - FSA: S > A: SCD, S beta plus thalassemia - FS: hemoglobin S: sickle cell anemia or sickle beta zero thalassemia - FSC: hemoglobin SC disease - FSV: sickle hemoglobin with variant hemoglobin - Alpha gene mapping - Alpha thalassemia trait influences the phenotype.

- Monitoring - CBC: Degree of anemia depends on genotype, leukocytosis, elevated platelet count, low mean corpuscular volume (MCV) with beta and alpha thalassemia, elevated MCV with hydroxyurea therapy, elevated reticulocyte count corresponding to degree of anemia. - Hemoglobin electrophoresis: hydroxyurea and transfusion therapy - Chemistry panel: elevated lactate dehydrogenase (LDH), unconjugated bilirubin, aspartate aminotransferase (AST) - Vitamin D 25-OH level - TCD annually: stroke risk, 2 " 16 years - Brain MRI/MRA: abnormal TCD or neurologic findings - Echocardiogram: pulmonary hypertension - Pulmonary function testing: obstructive lung disease - Ophthalmology: retinopathy - Neurocognitive testing: stroke or school delay

- Progenitor cell transplant is the only cure for SCD. - Full siblings: HLA typing for the patient and the prospective donor - Cord blood collection for full siblings - Consultation with a transplant physician familiar with transplantation for sickle cell anemia

- Fever - Patients with SCD and fever are presumed septic. - History, physical exam, CBC with reticulocytes, blood culture, chest x-ray, urine culture, and other cultures as indicated - Parenteral antibiotic: (ceftriaxone) until culture negative - Children younger than the age of 3 years, admitted to hospital - Older children and adolescents with a benign examination, no pulmonary infiltrate, or urinary tract infection: ceftriaxone follow-up in 24 hours

- Acute chest syndrome - Defined as a new pulmonary infiltrate frequently accompanied by hypoxia, pain, fever, and severe anemia - Treat for fever (above). - Type and cross - Transfusion for severe anemia, progressive infiltrate, hypoxia - Add microlide antibiotic. - Oxygen to maintain O2 saturation 95%. - Fluid overload can exacerbate pulmonary disease, monitor I and O. - Incentive spirometry q2h

- Pain (vaso-occlusive episode) - Severe pain is a medical emergency. - Hydration: 1.5 maintenance, avoid fluid overload. - Incentive spirometry: q2h - Pain assessment on pain scale - Analgesics - Mild pain: NSAIDs and mild oral opioids (20% will not metabolize codeine normally) - Moderate pain: may need parenteral therapy with opioids and ketorolac - Severe pain: admission with patient-controlled analgesia (PCA) parenteral opioids, may need antihistamine, ketorolac, H2 blocker with ketorolac

- Pain assessment after administration of medications - Adjunctive therapy: heating pad, visualization, distraction, other therapy

- Acute anemia - Parvoviral infection - History of decreased energy, pallor - Exam with tachycardia, pallor - CBC with reticulocyte count: anemia with reticulocytopenia - Type and cross - Transfusion for severe anemia or cardiovascular compromise - Parvoviral B19 titers - Isolation precautions

- Splenic sequestration - History of decreased energy, pallor - Exam with splenomegaly - CBC with reticulocyte count: anemia with reticulocytosis - Slow transfusion for severe anemia or cardiovascular compromise: Spleen releases red cells increasing hemoglobin and viscosity. - Splenectomy for life-threatening or repeated episodes: Immunize prior to splenectomy.

- Intracranial hemorrhage - Initially present with headache only - CT scan is diagnostic. - More common in adolescents - History of cerebral vascular disease - Neurosurgical consultation - Exchange transfusion is indicated. - Prognosis is poor if not aggressively treated. - Chronic transfusion for life

- Stroke risk - Abnormal TCD - Time average maximum mean velocity: 200 cm/s or greater - Transfusion to hemoglobin of 10 g/dL - MRI " MRA for cerebral vascular disease or ischemic brain injury - Transfusion for life with or without findings on MR

- Priapism - Diagnosis: unwanted erection with pain lasting for longer than 1 hour - Medical emergency - Initial management: pain management, intravenous hydration - Treatment with subcutaneous terbutaline has been used. - Definitive treatment: is aspiration and instillation of pseudoephedrine

- Chronic complications: - Cholecystitis - Avascular necrosis (hip and shoulder) - Obstructive pulmonary disease - Pulmonary hypertension - Renal disease (proteinuria) - Hyposthenuria (enuresis, dehydration) - Retinopathy (increased: SC disease) - School failure due to hospitalization - Cerebral vascular disease/infarcts

Sickle cell disease (SCD) is a hemoglobinopathy caused by a one base pair change leading to an amino acid change in the beta globin gene at the sixth position: glutamic acid to valine. The mutation allows the polymerization of hemoglobin in the red cell.

Pathophysiology

  • Disruption of the red cell membrane: leading to increased adhesion to vascular endothelium, activation of cytokines leading to activation of platelets and leukocytes, activation of the coagulation system leading to a hypercoagulable state and ultimately to vaso-occlusion. Red cells release red cell membrane as microparticles.
  • Red cell hemolysis: release of free hemoglobin, methemoglobin production, increased plasma ferric iron leading to oxidative stress, decreased nitric oxide leading to decreased production of cyclic GMP causing vasoconstriction, inflammation, and platelet activation

Epidemiology

  • The incidence of SCD is 1 in 500 African Americans, 1 in 36,000 Hispanics, with a lesser frequency in other ethnic groups. The incidence of sickle cell trait in African Americans is 1 in 14.
  • There are 70,000 " 100,000 affected individuals with SCD in the United States.

Risk Factors

Genetics

  • SCD is autosomal recessive.
  • Combinations leading to the disease state when inherited with hemoglobin S: SS, SC, S beta zero thalassemia, S beta plus thalassemia, S DLos Angeles, and S OArab are examples.

Diagnosis

History

  • At diagnosis:In the US, usually diagnosed on newborn screeningOften asymptomatic in early infancy (<6 months) due to protective effects of residual HbF production.Family historyHistory of irritability/painHistory of pallor
  • Subsequent to diagnosisSCD genotypeHistory of:SurgeryTransfusion (red cell phenotype)Hospitalizations (particularly ICU)Pain (sites and usual therapy)Stroke and/or transcranial Doppler (TCD) abnormalitiesAcute chest syndromeBaseline hemoglobin and pulse oximetryCurrent medication and therapy

Physical Exam

  • Pallor of anemia with flow murmur
  • Scleral icterus
  • Splenomegaly, hepatomegaly
  • Respiratory effort, decreased breath sounds, or wheeze: obstructive lung disease
  • Decreased range of motion: hip and shoulder avascular necrosis
  • Neurologic examination: stroke
  • Developmental assessment

Diagnostic Tests & Interpretation

Lab

  • DiagnosticAll states have newborn screening.F: thalassemia majorFA: normal hemoglobinFAS: A > S: sickle cell traitFSA: S > A: SCD, S beta plus thalassemiaFS: hemoglobin S: sickle cell anemia or sickle beta zero thalassemiaFSC: hemoglobin SC diseaseFSV: sickle hemoglobin with variant hemoglobinAlpha gene mappingAlpha thalassemia trait influences the phenotype.Beta gene analysisBeta thalassemia and beta variants
  • MonitoringCBC: Degree of anemia depends on genotype, leukocytosis, elevated platelet count, low mean corpuscular volume (MCV) with beta and alpha thalassemia, elevated MCV with hydroxyurea therapy, elevated reticulocyte count corresponding to degree of anemia.Hemoglobin electrophoresis: hydroxyurea and transfusion therapyChemistry panel: elevated lactate dehydrogenase (LDH), unconjugated bilirubin, aspartate aminotransferase (AST)Vitamin D 25-OH levelTCD annually: stroke risk, 2 " 16 yearsBrain MRI/MRA: abnormal TCD or neurologic findingsEchocardiogram: pulmonary hypertensionPulmonary function testing: obstructive lung diseaseOphthalmology: retinopathyNeurocognitive testing: stroke or school delay

Treatment

General Measures

  • Infection prophylaxis with oral penicillin 125 mg b.i.d. starting by 2 months of age, 250 mg b.i.d. at 36 months
  • Pneumococcal vaccine (23-valent at 2 and 5 years of age)
  • Meningococcal vaccine
  • Recommended routine immunizations
  • Folic acid and vitamin D supplementation as indicated
  • Parent teaching for fever, splenic sequestration, anemia, stroke, acute chest, and home pain management
  • Hospital pain management plan

Additional Therapies

  • Hydroxyurea: Patients who have two or more acute events leading to hospitalization a year or more frequent pain events not leading to hospitalization are considered for treatment.Beginning doses are between 15 and 20 mg/kg/24h If needed, increase dose by 5 mg/kg/24h every 2 " 6 months up to a maximum of 35 mg/kg/24h or 2,500 mg/24h (whichever is less).Monitor initially at 2 weeks and 1 month.Without toxicity, monitor every 2 months.
  • Red cell transfusion can prevent complications, morbidity, and are lifesaving.Phenotypically matched red cells (for ABO, D, C, c, E, e, Kell) decreases alloimmunization.Optimum hemoglobin is 9 " 10 g/dL, higher levels increase viscosity, decrease oxygenation.Percentage of hemoglobin S should be <30% in acute disease, for stroke and stroke prevention.With elevated hemoglobin or when a low percent S is indicated, exchange transfusion is required.Transfusion iron overload: All patients are monitored and treated with oral chelation.
  • Progenitor cell transplant is the only cure for SCD.Full siblings: HLA typing for the patient and the prospective donorCord blood collection for full siblingsConsultation with a transplant physician familiar with transplantation for sickle cell anemia

Inpatient Considerations

  • FeverPatients with SCD and fever are presumed septic.History, physical exam, CBC with reticulocytes, blood culture, chest x-ray, urine culture, and other cultures as indicatedParenteral antibiotic: (ceftriaxone) until culture negativeChildren younger than the age of 3 years, admitted to hospitalOlder children and adolescents with a benign examination, no pulmonary infiltrate, or urinary tract infection: ceftriaxone follow-up in 24 hours
  • Acute chest syndromeDefined as a new pulmonary infiltrate frequently accompanied by hypoxia, pain, fever, and severe anemiaTreat for fever (above).Type and crossTransfusion for severe anemia, progressive infiltrate, hypoxiaAdd microlide antibiotic.Oxygen to maintain O2 saturation 95%.Fluid overload can exacerbate pulmonary disease, monitor I and O.Incentive spirometry q2h
  • Pain (vaso-occlusive episode)Severe pain is a medical emergency.Hydration: 1.5 maintenance, avoid fluid overload.Incentive spirometry: q2hPain assessment on pain scaleAnalgesicsMild pain: NSAIDs and mild oral opioids (20% will not metabolize codeine normally)Moderate pain: may need parenteral therapy with opioids and ketorolacSevere pain: admission with patient-controlled analgesia (PCA) parenteral opioids, may need antihistamine, ketorolac, H2 blocker with ketorolacPain assessment after administration of medicationsAdjunctive therapy: heating pad, visualization, distraction, other therapy
  • Acute anemiaParvoviral infectionHistory of decreased energy, pallorExam with tachycardia, pallorCBC with reticulocyte count: anemia with reticulocytopeniaType and crossTransfusion for severe anemia or cardiovascular compromiseParvoviral B19 titersIsolation precautions
  • Splenic sequestrationHistory of decreased energy, pallorExam with splenomegalyCBC with reticulocyte count: anemia with reticulocytosisSlow transfusion for severe anemia or cardiovascular compromise: Spleen releases red cells increasing hemoglobin and viscosity.Splenectomy for life-threatening or repeated episodes: Immunize prior to splenectomy.
  • StrokeDiagnosis by history and physical examinationTreatment should not be delayed for imaging.Evidence suggests initial exchange transfusion, to hemoglobin of 9 " 10 g/dL, percent hemoglobin S of less than 30%, leads to improved long-term outcome.All patients should have brain MRI and MRA urgently and be evaluated by neurology and physical therapy.Eventually, all patients should have neuropsychological testing.Chronic transfusion for life
  • Intracranial hemorrhageInitially present with headache onlyCT scan is diagnostic.More common in adolescentsHistory of cerebral vascular diseaseNeurosurgical consultationExchange transfusion is indicated.Prognosis is poor if not aggressively treated.Chronic transfusion for life
  • Stroke riskAbnormal TCDTime average maximum mean velocity: 200 cm/s or greaterTransfusion to hemoglobin of 10 g/dLMRI " MRA for cerebral vascular disease or ischemic brain injuryTransfusion for life with or without findings on MR
  • PriapismDiagnosis: unwanted erection with pain lasting for longer than 1 hourMedical emergencyInitial management: pain management, intravenous hydrationTreatment with subcutaneous terbutaline has been used.Definitive treatment: is aspiration and instillation of pseudoephedrine

Ongoing Care

Prognosis

The prognosis for children with sickle cell disease has improved dramatically due to hydroxyurea therapy, increased use of blood transfusion, and screening. Transition to adult care is a priority.

  • Chronic complications:CholecystitisAvascular necrosis (hip and shoulder)Obstructive pulmonary diseasePulmonary hypertensionRenal disease (proteinuria)Hyposthenuria (enuresis, dehydration)Retinopathy (increased: SC disease)School failure due to hospitalizationCerebral vascular disease/infarcts

Additional Reading

  • Ballas SK. New era dawns on sickle cell pain. Blood. 2010;116(3):311 " 312. [View Abstract]
  • Bernaudin F, Verlhac S, Arnaud C, et al. Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort. Blood. 2011;117(4):1130 " 1140. [View Abstract]
  • Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in SCD (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet. 2013;81(9870):930 " 938. [View Abstract]
  • Thornburg CD, Files BA, Luo Z, et al. Impact of hydroxyurea on clinical events in the BABY HUG trial. Blood. 2012;120(22):4304 " 4310. [View Abstract]

Codes

ICD09

  • 282.60 Sickle-cell disease, unspecified
  • 282.5 Sickle-cell trait
  • 282.41 Sickle-cell thalassemia without crisis
  • 282.61 Hb-SS disease without crisis

ICD10

  • D57.1 Sickle-cell disease without crisis
  • D57.3 Sickle-cell trait
  • D57.40 Sickle-cell thalassemia without crisis
  • D57.80 Other sickle-cell disorders without crisis

SNOMED

  • 417357006 Sickling disorder due to hemoglobin S (disorder)
  • 16402000 Sickle cell trait (disorder)
  • 36472007 Sickle cell-thalassemia disease (disorder)
  • 416290001 Hemoglobin S sickling disorder without crisis (disorder)
  • 127041004 Sickle cell-beta-thalassemia (disorder)

FAQ

  • Q: When can I stop penicillin prophylaxis?
  • A: Most morbidity and mortality from infections in sickle cell anemia occur in the first 5 years of life. The risk of pneumococcal sepsis decreases with age but continues to be a significant risk of morbidity and mortality. Patients with surgical splenectomy need penicillin prophylaxis for life.
  • Q: Are phenotypically matched red cells necessary for transfusion?
  • A: Historically, the incidence of red cell alloimmunization is 30% for patients with SCD who do not receive phenotypically matched red cells. By providing phenotypically matched red cells, the rate of alloimmunization is significantly decreased.