Sickle Cell Disease Part I & II

1. Sickle Cell DiseasePart I & II MR 8/7/09 J. Chen

2. Introduction • Sickle Cell Disease is a chronic hemolytic anemia- includes hemoglobin varients: • SS • SC • S-beta thalassemia • SO Arab • SD • Characterized by hemolysis, vascular occlusion, organ ischemia, end organ damage • Genetic Defect-Substitution of valine for glutamate at codon 6 on chromosome 11 • AutosomalResessive

4. Epidemiology • 1:375 Black newborns • 1:12 Black has sickle cell trait • SCD-SS (60%), SCD-SC (25-30%) • Geographic distribution corresponds to distribution of malaria

5. Diagnosis • NB screen in 44 states • 93.1%-100% sensitivity • 99.9% • Other states HbEp should be done <3mo for high risk • Hemaglobin electrophoresis is definitive test along with DNA analysis • Other techniques: • Isoelectric focusing • High-performance liquid chromatography • Prenatal Diagnosis CV sampling (1st trimester), amniocentesis (2nd trimester) • Sickledex not recommended in newborns 2nd high false negative

6. Clinical • Clinical manifestations appear within first year as fetal Hb concentration declines • Young children are at risk for bacterial infections, splenic sequestration, stroke • Adolescents and adult begin to experience end organ damage: Pulm HTN, renal disease, strokes, avascular necrosis, leg ulcers, chronic pain syndrome

7. Infection • Functional Asplenia seen as early as 2 months • By 1 year of age ~30% have functional asplenia, by 6 years ~90% • Organisms that pose the greatest danger include encapsulated respiratory bacteria, particularly Streptococcus pneumoniae (400x higher)

8. Infection • Consider osteomyelitis when dealing with a combination of persistent pain and fever. • Bone that is involved with infarct-related vaso-occlusive pain is prone to infection. • Staphylococcus and Salmonella are the 2 most likely organism • Meningitis is 200 times more common in children with HbSS.

9. Management of Infection • Prevention • Heptavalent pneumococcal vaccine 2,4,6 mo age • 23-valent pneumococcal vaccine at 2yr and 5ys • Penicillin prophylaxis no later than 3month-5years (125mgBID until 3y then 250mgBID)

10. Management of infection • Treatment • early recognition; aggressive diagnostic evaluation including CBC count, urinalysis, chest radiographs, and blood cultures; • prompt administration of intravenous antibiotics active against S pneumoniae; and close observation. • <12 months with a temperature > 39C who appear toxic, with an infiltrate on chest radiograph and an elevated WBC count, should be admitted to the hospital. • Consider only outpatient treatment if no high-risk features appear on history, physical examination, or laboratory evaluation; if the child is older than 12 months; and if outpatient follow-up care can be ensured.

11. Acute Chest Syndrome • Definition-radiologic appearance of a new pulmonary infiltrate and fever • +/- Hypoxia • ~50% experience 1 episode • ~35% of admissions

12. Acute Chest-Management • Broad-spectrum antibiotics including a cephalosporin and macrolide • O2, hydration, incentive spirometry • Transfusion therapy for associated hypoxia or Hct<18

13. Acute Chest • Multiple ACS episodes may lead to chronic restrictive pulmonary disease and possible pulmonary HTN. • Children with recurrent ACS should be evaluated by PFT’s • Exchange transfusion reserved for severe ACS • Recurrent ACS may consider Hematopoietic stem cell transplant

14. VOC pain crisis • Pain, resulting from vascular occlusion and ischemia • the most common feature of sickle cell disease and can affect any body part. • Can be debilitating and affect school, job, social • Bone pain is often due to bone marrow infarction. • During the first 18 months of life, the metatarsals and metacarpals can be involved, presenting as dactylitis or hand-foot syndrome.

15. Dactylitis, Hand-Foot Syndrome • Strong predictor of overall severity (ie, death, risk of stroke, high pain rate, recurrent acute chest syndrome). • Episode before age 1 year are at high risk of a severe clinical course.

16. VOC crisis cont… • Episodes may be triggered by: • Infection • Temp extremes • Dehydration • Stress • No identifiable cause • Average length of stay-4days

17. VOC-Management • Aggressive hydration: 1 ½ Maintanence • D51/2 or 1/4NS • Aggressive pain management • Moderate pain: Acetominophen +/- codein, NSAIDS • Severe pain: Opioids (morphine, hydromorphone) • PCA • >10days opioids may become tolerant and need to be weaned • Methadone • Physical therapy, relaxation therapy • Hydroxyurea-decrease frequency of VOC and need for blood transfusion by 50%

18. To be Continued • Part II: • Acute Splenic Sequestration • Cerebrovascular Disease • Chronic Organ Damage • Osteonecrosis • Retinopathy • Priapism • Cholecystitis • Pulm HTN • Future Therapy

19. Acute Splenic Sequestration • sudden enlargement of the spleen along with a greater than 2-g/dL (20-g/L) decrease in Hb from baseline with reticulocytosis. • sudden circulatory collapse and was a common cause of death prior to early diagnosis and education through newborn screening programs. • <3y with SS or other varients • Recurrence is common

20. Cerebrovascular Disease • 11% of patients who have Hb-SS by age 20 years, and silent infarction is detected on neuroimaging studies in another 22%. • The peak incidence of overt stroke occurs in children between 2 and 10 years of age • TCD-Flow Velocity >200cm/sec • Screening recommended annually for all children with Hb-SS or S-beta Thal ages 2-16y

21. Cerebrovascular Disease • Current guidelines recommend indefinite transfusion therapy for patient with abnormal TCD

22. Priapism • sustained, painful, and unwanted erection • According to one study, the mean age at which priapism occurs is 12 years • By age 20 years, as many as 89% of males with sickle cell disease have experienced one or more episodes of priapism. • Recurrent episodes of priapism can result in fibrosis and impotence, even when adequate treatment is attempted. • Prolonged priapism is an emergency that requires urologic consultation.

24. Therapies • Hydroxyurea • Elevates concentration of fetal Hb • Decrease frequency of VOC, ACS, hospital admissions, blood transfusion by 50% • >5yr age with severe complications

25. Transfusion • Simple PRBC transfusion • Aplastic Crises • Splenic Sequestration • ACS • Preoperatively • Exchange transfusion reserved for stroke, severe ACS, unremitting priapism, preop cardiac/neuro/retinal surgery

26. Hematopoietic Stem Cell Transplant • Only Cure • Requires human leukocyte antigen-matched sibling donor • Indications • Stroke • Positive TCD result • Multiple ACS or VOC episodes • Event free survival 95% • Only 14% have HLA matched sibling donor

27. Future Therapy • HSCT with umbilical cord blood transplant, haptoidentical transplants • Finding new fetal Hb-modulating agents • Modulating red blood cell dehydration • Nitric oxide therapy and corticosteroid for ACS

28. A 14-month-old boy who has sickle cell disease (SCD) developed a fever to 104°F (40°C) 3 hours ago. He has had nasal congestion for 2 days but no fever. He had been drinking normal amounts of fluids until he became febrile and since has taken only very small amounts. His physical examination reveals normal blood pressure. Oxygen saturation is 96% in room air. The only abnormalities are possible crackles over the right upper lobe and a spleen palpable 1 to 1.5 cm below the left costal margin. Complete blood count reveals a hemoglobin of 6.9 g/dL (69 g/L), white blood cell count of 18x103/mcL (18x109/L), and platelet count of 675x103/mcL (675x109/L). Blood culture is obtained. Of the following, the most appropriate initial step is to:

29. A. Administer a bolus of normal saline over 1 hour. • B. Administer intravenous ceftriaxone. • C. Ensure that prophylactic penicillin has been administered and is continued. • D. Obtain a chest radiograph. • E. Transfuse packed red blood cells.

30. Answer: B.

31. The mother of a 2-year-old boy who has SCD noted decreased activity and increasing pallor in the boy over the past 8 hours. She has been taught splenic palpation, and she reports that his spleen usually is not palpable, but was 3 inches below the rib cage before leaving home. Physical examination reveals a pale, lethargic child. His temperature is 100.4°F (38°C), heart rate is 195 beats/min, respiratory rate is 40 breaths/min, and blood pressure is 60/32 mm Hg. He is crying, and the edge of his spleen appears to be 6 cm below the left costal margin. A blood count, blood culture, and cross-match are obtained. Of the following the most appropriate next step is:

32. A. A bolus of intravenous normal saline. • B. Intravenous ceftriaxone followed by vancomycin. • C. Transfusion of antigen-matched packed red blood cells. • D. Transfusion of uncrossed-matched, O-negative packed red blood cells. • E. Urgent ultrasonography to confirm splenic enlargement.

33. Answer: A

34. Parents of a newborn in whom SCD was diagnosed by newborn screening come to you for counseling and education. Although they understand that the first painful event is not likely to occur for at least several months, they are concerned about their child's future if painful events should begin early. Which of the following types of pain is a clinical predictor of severe disease if it occurs before 1 year of age?

35. A. Abdominal tenderness. • B. Chest tenderness and increased respiratory rate. • C. Hip pain. • D. Painful swelling of the hands and feet. • E. Priapism.

36. Answer-D.