Disclosure info CHILDREN WITH SICKLE CELL DISEASE (SCD): MANAGEMENT AND TREATMENT Rebecca J. Patterson, RN, PhD, PPCNP-BC UAMS, College of Nursing and Arkansas Children’s Hospital What is Sickle Cell Disease? Dr. Patterson has no relevant financial or nonfinancial relationships to disclose. No potential conflict of interest in relation to the presentation within the past 12 months. Who Is Affected? • Most common in persons with African ancestry • Found in Mediterranean, Middle Eastern, Indian An inherited hemoglobin abnormality of the globin chains which causes red blood cells to irreversibly “sickle” in some situations Autosomal Recessive Inheritance groups • Hispanics • Caucasian Screening Tools/Types of SCD • Newborn Screening (All states) • Followed with Hgb electrophoresis MOTHER As AA FATHER As As As SS Hgb FS (Hgb SS) Hgb FSA2 (Hgb SBeta0thalassemia) Hgb FSC (Hgb SC) Hgb FSA (Hgb SBeta+thalassemia) Hgb SS with persistent Fetal Hemoglobin Age Affects Sickle cell globin abnormality • Most Hgb at birth is fetal type (Hgb F) • Bon marrow “switches” to adult form at about 12 to 18 months • Never “outgrow” disease • More organs affected as get older Sickle cell globin abnormality “Heme” + “Globin” = Hemoglobin Heme = Fe containing & oxygen binding area of Hgb Globin in normal Adult (Hgb A) : 2 alpha chains/2 beta chains Polymerization • Beta globin chain has 146 amino acids • Beta S has a single point mutation at amino acid position 6-B6- valine substituted for glutamine • This single point mutation, completely alters physical/chemical properties of the entire Hemoglobin molecule • De-oxygenation leads to “polymerization” Normal hemoglobin exists as solitary units whether oxygenated or deoxygenated (upper panel). In contrast, sickle hemoglobin molecules adhere when they are deoxygenated, forming sickle hemoglobin polymers (lower panel). www.harvard.edu Sickled cell formation Sickle cell disease results in damage to all organs in the body. • RBC are usually round and flexible, move easily throughout the body. • Sickle RBC are stiff and sticky-more likely to get “stuck” in blood vessels. • Causes injuries to lining of vessels • Can happen anywhere in the body. Sickle cell disease results in damage to all organs in the body (cont) • Leads to poor perfusion of tissues • Poor oxygenation then ischemic damage • Pain • Organ injury • Also leads to shortened red cell survival- normal 100-120 days; sickle cell anemiausually less than 10 days • Anemia, jaundice Normal RBCs versus Sickle Cell RBCs Normal RBC • Disc-shaped • Soft (like a bag of jelly) • Easily flow through small blood vessels • Lives for 120 days Sickle Cell • Sickle shaped • Hard (like a piece of wood) • Often get stuck in small blood vessels • Lives for 20 days or less Red Blood Cells - Retics Reticulocytes, or Retics are young red cells just released from the bone marrow. The Retic count tells us how the marrow factory is doing. Normal is 0.5 to 1.5% Children with SCD can have retics up to 10-20 or higher. Normal vs. Sickle red cells If no oxygen, then pain and damage occurs are stickier Sticky red cells block blood flow, then pain and damage occurs Complications of Sickle Cell Disease Stroke, silent infarcts, and decreased neurocognitive function Hematology (anemia, leukocytosis)) Growth and maturation Retinopathy Acute chest syndrome Pain Pulmonary hypertension Splenic function Infections AVN Psychological problems Priapism Infections • Increased risk of infection in sickle cell disease • Spleen – first organ severely damaged • Locations of immunity to certain bacteria • Streptococcus pneumoniae • Haemophilus influenzae type B • Pneumococcus • Younger Children more at risk • Sepsis • Pneumonia • Meningitis Leg ulcers Fever: Evaluate promptly Fever represents sepsis until proven otherwise. Infections Prophylactic penicillin < 3 yo – 125 mg PenVK po bid > 3 yo – 250 mg Pen VK po bid Evaluate promptly and consider CBC, reticulocyte count, blood culture and chest X-ray. Broad spectrum antibiotics Pediatric Mortality in Sickle Cell Disease (by age and time period, U.S, 1983-2002) Transient Aplastic crisis Prophylactic penicillin recommended (1986) Treatment: • Close observation • Consider need for transfusion Yanni, et al, J. Pediat. 154:541, 2009 Abdominal Pain - Splenic Sequestion • Intrasplenic trapping of blood within the spleen • precipitous fall in hemoglobin level • which can lead to shock • Left sided abdominal pain (Abdominal distention) • May be associated with fever, pain, vomiting, and respiratory symptoms (Dyspnea). • Treatment • Caregiver education is important. CNS – Stroke • Incidence of stroke: 5-12%. • Transcranial Doppler screening • Treatment of stroke • True emergency • Initiate treatment is rapidly lowering hemoglobin S to less than 30%. • Long term transfusion therapy. (Apheresis) Transcranial Doppler Ultrasonography (TCD) Screening for Increased Stroke Risk Painful Episodes • Common in sickle cell disease • Typically involve limbs, abdomen, lower back • Precipitating factors Dactylitis - Hand Foot Syndrome • Ages six months - two years. • May be first presentation to ER o Illness/infection • Treated with fluids o Dehydration and pain medication. • Consider osteomyelitis o Cold o Stress o Infection o Menses Treatment of Painful Crises (Home Management) • Treat the cause if one identified. (i.e. Infection) • Drink fluids liberally • Warm baths, heating pads, massage • Ibuprofen (10mg/kg) PO every six hours – fixed dosing. • Oral Oxycodone if needed. Remember bowel regimen Treatment of Painful Crises (Hospital/ER management) • Treat the cause if one identified. (i.e. Infection) • Administer IV fluids liberally • Administer morphine or other appropriated drug intravenously in full therapeutic doses at 2 to 4 hour intervals. • NOTE: PCA pump offers more consistent blood levels and better pain control • Fixed dosing initially, no PRN during pain episode • Consider adjuvant non-steroidal antiinflammatory Transfusion Indicated Transfusion Probably Not Indicated • Symptomatic episodes of acute anemia • Raising the customary hemoglobin • Severe symptomatic chronic anemia concentration • Uncomplicated painful episodes • Uncomplicated pregnancy • Minor surgery local anesthesia • Ex. splenic sequestration, Aplastic crisis • Prevention of recurrent strokes • Acute chest syndrome with hypoxia • Pre-Anesthesia • Example - Surgery with general anesthesia Pulmonary – Acute Chest Syndrome Iron Overload (Clinically Similar to Pneumonia) • Secondary to recurrent transfusions • Avoid iron supplementation • Two meds available for iron chelation: • Deferasirox (Exjade-PO) • Deferoxamine (Deferoxamine-SQ) • • • • • • Cough Chest pain Fever Tachypnea Grunting Oxygen requirement Treatment of Acute Chest Acute chest & Pneumonia: hard to tell the two apart so both are treated. Oxygen for O2 saturation < 90% Antibiotics – Broad spectrum Fluid management Respiratory therapy – Bronchodilators, Incentive Spirometry • Pain management • Transfusion therapy • • • • Cardiac Manifestations - Anemia Need for O2 delivery: • Leads to cardiac enlargement. • On exam, • Heart Murmurs Renal • Hyposthenuria • Hematuria • Renal papillary necrosis • Proteinuria • Renal failure Gall Bladder • Cholecystitis – • chronic hemolysis with increased bilirubin turnover • leads to increase in gallstones • Onset as early as age 2 – 4 years • 30% by age 18 Dermatologic: Leg Ulcers Focal Bone Pain Skeletal changes • Bone infarction, sickle • Avascular necrosis arthritis, and aseptic necrosis of the femur or humerus. • Consider osteomyelitis if febrile or increased WBC • X-ray, bone scan, MRI may help • Avascular necrosis of the femoral head of the humeral head • Treatment: Surgical versus non-surgical. Priapism Ophthomologic manifestations • Persistent, painful erection • Retinopathy • Hyphema • Longer than three to four hours is medical emergency • 30% of males, under the age of 20 years, reported having had at least one episode of priapism • Treatment: Needle decompression, medications (i.e. ephedrine) Hydroxyurea Hydroxyurea • Hydroxyurea is the ONLY FDA approved therapy for preventing pain crises related to SCD • Anti-neoplastic agent in the 1960’s • Anti-sickling agent in the 1980s • Primary clinical effect • Induction of Hgb F to productive levels Mechanism Of Action Raises hemoglobin F and reduces the formation of hemoglobin S Reduction in neutrophils, monocytes and reticulocytes Before HU therapy On Therapy Produces Increased hemoglobin Increased hemoglobin F Decreased reticulocytosis Increased MCV Decreased bilirubin Decreased white count Decreased LDH Hydroxyurea: Benefits: Decreased painful episodes Decreased anemia Decreased acute chest syndrome Decreased hospitalizations Decreased transfusions Long term benefits Negatives Increased visit requirement as dosage titrated to maximum tolerated dose Need for daily medication Long term risks for chronic organ dysfunction? Maintenance of Normal Life • Psychosocial stress of chronic disease Normal child, with Sickle Cell Disease, needs normal life • Activities of daily living • Peers • School/play • Employment • Normal intelligence • Families Immunizations Pediatric Mortality in Sickle Cell Disease (by age and time period, U.S, 1983-2002) Child need to have all of the recommended shots for children plus: • Pneumovax/Prevnar • Hepatitis A • Hepatitis B • Flu vaccine Prophylactic penicillin recommended (1986) Yanni, 2009 Growth and Developmentrowth and Development: School • Some children with sickle cell disease are shorter and • Multiple absences may cause child to fall • • • • thinner than their similarly age peers This difference is usually only temporary They may have delayed onset of puberty Does not affect intelligence Expect child to do normal activities • Should not be missing “lots of school” behind • May need tutor or increase time to complete assignments • May participate in PE • No high impact exercises unless steps taken to avoid dehydration • Activities in extreme heat or cold should be avoided. Needs During School • May need ibuprofen while at school for pain • Hydration • Needs 64 to 80 ounces of liquids per day • Fluids between classes RESEARCH • Frequent bathroom breaks • Notify parents and seek immediate medical attention: • complains of severe pain • acute weakness or paralysis of one side of body • excessively sleepy or unresponsive. Research - Hydroxyurea • Phase I/II pilot study of hydroxyurea in 28 infants • Objectives: • to determine the feasibility of hydroxyurea administration • its toxicity, hematology effects, and effect on spleen function over two years. • HU dose 20mg/kg/day, liquid preparation • Results: ↑ Hb, ↑ Hb F, ↓ WBC (Wang, 2011) Baby Hug Randomized Phase III clinical trial • Objectives: • Primary: • to determine whether hydroxyurea can prevent or reduce chronic damage to the spleen and kidneys in very young children • Secondary: • to investigate safety; to determine hematologic effects and effects on other measures of organ function • to examine effects on adverse events Baby HUG Conclusions (2011) BABY HUG Follow-Up Study • Hydroxyurea does not prevent splenic or renal • Goals: dysfunction. • HU does not have significant toxicity other than moderate, transient neutropenia. • Hematologic effects of HU may lead to a more favorable prognosis? - ↑Hb → ↓stroke - ↑HbF → ↓pain, ACS, mortality - ↓WBC → ↓stroke, ACS • HU decreases incidence of pain and dactylitis, and probably acute chest syndrome, transfusions and hospitalizations Hydroxyurea and the Future • Continue to follow cohorts such as BABY-HUG and HUSTLE • Offer HU to all 1 or 2 year-olds with Hgb SS or Sβ0thalassemia • Determine what factors are associated with decision to accept or decline HU treatment • Examine the effects of HU on the brain through serial evaluations • Examine the effects of HU on QOL • Determine if HU can be used effectively on a global scale • To identify possible long-term HU toxicities in children who participated in BABY HUG • To determine if prolonged treatment with HU changes risks and benefits. • Open-label HU offered after end of randomized trial; dose escalation allowed. • “Special” evaluations: • spleen scan, abdominal ultrasound, neuropsychologic testing, MRI/MRA of brain, pulmonary function, echocardiography, urine microalbumin, QOL assessment, and genotoxicity Ongoing Multicenter CNS Trials: • SITT – Can chronic transfusion prevent stroke and additional silent infarcts? • TWiTCH – Can HU prevent 1°stroke in patients with abnormal TCD velocities? • HUSTLE – Hydroxyurea Study of Long Term Effects – prospective observational study of children treatd with HU based on clincal severity, which attempts to evaluate the longterm cellular and molecular effects of HU. Additional Research Research (cont) • Genetic factors affecting sickle cell disease • New treatments for pain • • • • • symptoms Regulation of hemoglobin production Development of drugs to increase fetal hemoglobin production Transplantation of blood-forming stem cells Bone Marrow Transplants Gene therapy • Optimal uses of blood transfusion • Management of iron overload associated with blood transfusions • Development of animal models for preclinical studies Gene Therapy Treatments for SCD - Conclusions • Treatment options much better than 20 years ago Research is underway to fix the basic genetic defect • putting back the correct amino acid in the hemoglobin before or shortly after birth. • would result in a cure of the root of the problem. • method to do this safely is still undergoing work in many research labs around the world • Chronic transfusion useful for specific problems – especially involving the CNS • Curative therapy with HSCT expanding; gene therapy not yet ready for large-scale trials • Hydroxyurea has best potential for treatment of most patients with SCD, particularly for decreasing vaso-occlusive complications and mortality—and it should be considered for all HbSS patients Questions? Thank you! Websites References • SickleCellKids.ORG – www.sicklecellkids.og • Centers for Disease Control and Prevention. (CDC) (2013). Sickle cell • Sickle Information Center - http://www.scinfo.org/ • National Heart, Lung and Blood Institute • http://www.nhlbi.nih.gov/health • Sickle Cell Disease Association of America, Inc. • http://www.sicklecelldisease.org • Centers for Disease Control • http://www.cdc.gov/ncbddd/sicklecell/ disease. Retrieved from http://www.CDC.gov/ncbddd/sicklecell • Hamptom, R., (2014) Ophthalmologic Manifestations of Sickle Cell Disease. Retrieved from http://emedicine.medscape.com • Hankins, J.S., Ware, R.E., Rogers, Z.R., Wynn, L.W., Lane, P.A., Scott, J.P., Wang, W.C. (2005) Long term hydroxyurea therapy for infants with sickle cell anemia: the USOFT extension study. Blood, 106(7) 2269-2275. • Heeney, M., & Russell, W. (2010). Hydroxyurea for children with sickle cell disease. Hematology Oncology Clinics of North America, 24(1), 199-214. • How does sickle cell cause disease? (2002) Retrieved from http://harvard.edu • Lerma, E.V. (2012) Renal Manifestations of sickle cell disease. Retrieved from http://emedicine.medscape.com . References (cont.) References (cont.) • National Heart, Lung, and Blood Institute (NHLBI). (2013). • Ware, R.E., and Helms, R.W. (2012) Stroke with Sickle cell anemia. Retrieved from http://www.nhlbi.nih.gov/health • Nolan, B.G., Wyszynske, D.F., Farrer, L.A., Steinberg, M.H. (2005). Hemolysis-associated priapism in sickle cell disease. Blood, 106(9), 3264-3267. • Sickle Cell Disease Association of America, Inc. (SSDAA). (2013). About sickle cell disease. Retrieved from http://www.sicklecelldisease.org • Wang, W.C., Ware, R.R., Miller, S.T., Rath, V., Casella, J.F., Minniti, C.P., … Thompson, B.W. (2011) Hydroxycarbamide in very young children wit sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). The Lancet, 377(5), 1663-1672 transfusions changing to Hydroxyurea (SWiTCH). Blood, 119(17), 3925-3932. • Wright, J., & Ahmedzai, S. (2010). The management of painful crisis in sickle cell disease. Current Opinion in Supportive and Palliative Care, 4(2), 97-106. • Yanni,E., Grosse, S.D., Yang, Q., & Olney, R.S. (2009). Trends in pediatric Sickle cell disease-related mortality in the United States, 1983-2002. Journal of Pediatrics, 154(4), 541-545.