Historic and Current Complications in Children with Sickle Cell Disease

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1 Historic and Current Complications in Children with Sickle Cell Disease Trish McMahon Peterson RN, MSN, CPNP Thomas C. Hofstra MD Children's Hospital Los Angeles Comprehensive Sickle Cell Program Children's Center for Cancer and Blood Disease Sickle Cell Disease Educational Seminar September 9, 2016

2 Objectives Describe the pathophysiology and clinical manifestations of sickle cell disease Describe historic and current trends in Sickle cell management in the pediatric population Understand possible curative treatments 2

3 Sickle Cell Disease β chain defect caused by a substitution of Valine for Glutamic Acid at the 6th position of the beta chain on Chromosome #11 QUALITATIVE anemia - the hemoglobin is flawed by the amino acid substitution Disease of Hemolysis- life span of RBC is shortened from 120 days, to days. Deoxygenation, dehydration, acidosis, stress, infection, temperature changes, causes Hb S to change shape- polymerizes, and becomes insoluble 3

4 Sickle cell disease 240,000 children born annually in Africa with SCD 80 % do not survive to their second birthday Estimated 80,000 affected in USA, 6900 in Ca. 97 % of children in the US survive to age 18 1/365 African American, 1/16,300 Hispanics

5 SCD Survival in Children (Survival Normal) Quinn et al, 2010 Blood 115(17) 3447

6 Infection in Sickle Cell Disease Historically, infection is a major cause of mortality in SCD, particularly in children, and it was implicated in 20 50% of deaths in prospective cohort studies over the last 30 years. Worldwide, it remains the leading cause of death, particularly in less developed countries J of Inter Infections 2010, Booth C. Reduced splenic function- children are prone to sepsis- esp. Encapsulated infections- ie. Pneumococcus, Haemophilus, salmonella. 6

7 Infection-PROPS I The Prophylactic Penicillin Study (PROPS I) took place in 1983 to see if daily penicillin decreases serious pneumococcal blood infections in children under 3 yrs with SCD. It showed an 84% reduction in infection in children on penicillin. PROPS2 Penicillin Prophylaxis in SCD II study (PROPS II) showed that daily penicillin can be safely stopped after 5 yrs because there was not a significant benefit for taking penicillin compared to a placebo.

8 Screening for Sickle-Cell Anemia Expanded; 1990 The demonstration in 1986 that penicillin greatly reduces the risk of serious blood infections provided a powerful incentive for NBS for SCD Newborn screening for sickle cell disease began in the united states in the early 1970 s Identifies about 2,000 infants per year in the USA

9 Public Health Rep Mar-Apr; 128(2):

10 Pneumococcal vaccines Made from inactivated/killed bacteria 7-valent conjugate vaccine (PCV-7) available since valent pneumococcal vaccine (PCV-13) received FDA approval Feb valent polysaccharide vaccines (PPSV23) > 2 yrs available since the 1970s

11 Pneumococcal valent conjugated pneumococcal vaccine (serotypes 1, 3, 5, 6A, 7F, 19 A + PCV strains) Based on 2007 data, > 60 % IPD caused by these additional strains Infant schedule same as for PCV-7 (four doses at 2, 4, 6 and months)

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14 Who should get vaccinated this season? Everyone 6 months of age and older should get a flu vaccine every season. This recommendation has been in place since February 24, 2010 when CDC s Advisory Committee on Immunization Practices (ACIP) voted for universal flu vaccination in the United States to expand protection against the flu to more people. Vaccination to prevent influenza is particularly important for people who are at high risk of serious complications from influenza. 14

15 Can I get the Flu from the Flu shot? The viruses in the flu shot are killed (inactivated), so you cannot get the flu from a flu shot. Some minor side effects that may occur are:soreness, redness, or swelling where the shot was given Fever (low grade) Aches 15

16 The most important factor in effective vaccine risk-benefit communication is a trusting relationship with you-the healthcare provider! The Biggest Difference Is You

17 Sickle Cell Disease: Stroke Overt stoke occurs in about 10-15% of children with SCD 67% recur if untreated Significant mortality Lateralizing neurologic signs Headache Seizures Silent strokes occur in 37% by age 14yrs Bernaudin, et al, 2011, Blood 117(4) 1130 Hulbert et al, 2011, Blood 117(3) 772

18 Stroke Prevention All SS and Sβ0 thal children should be screened annually for elevated transcranial Doppler Velocity (TCD) Elevated TCD (>180/200) implies 30% chance of stroke within 3 years. (70% will not have a stroke) Chronic transfusion indefinitely if TCD velocity > 200 cm/sec by Nicolette; 180 cm/sec by Acuson 18

19 Transfusion therapy key intervention for decreasing morbidly and mortality in patients with SCD Despite the recognized benefits of transfusion therapy it is not without risk Transfusion Therapy 19

20 History of Transfusion Medicine 1628 English physician William Harvey discovers the circulation of blood. Shortly afterward, the earliest known blood transfusion is attempted The first recorded successful blood transfusion occurs in England: Physician Richard Lower keeps dogs alive by transfusion of blood from other dogs Jean-Baptiste Denis in France and Richard Lower in England separately report successful transfusions from lambs to humans. Within 10 years, transfusing the blood of animals to humans becomes prohibited by law because of reactions. 20

21 History of Transfusion Medician 1818 James Blundell, a British obstetrician, performs the first successful transfusion of human blood to a patient for the treatment of postpartum hemorrhage. Using the patient's husband as a donor, he extracts approximately four ounces of blood from the husband's arm and, using a syringe, successfully transfuses the wife. Between 1825 and 1830, he performs 10 transfusions, five of which prove beneficial to his patients, and publishes these results. He also devises various instruments for performing transfusions and proposed rational indications. 21

22 History of Transfusion Medicine US physicians transfuse milk (from cows, goats, and humans) Saline infusion replaces milk as a blood substitute due to the increased frequency of adverse reactions to milk 1907 Hektoen suggests that the safety of transfusion might be improved by cross matching blood between donors and patients to exclude incompatible mixtures. Reuben Ottenberg performs the first blood transfusion using blood typing and cross matching in New York. Ottenberg also observed the Mendelian inheritance of blood groups and recognized the universal utility of group O donors. 1939/40 The Rh blood group system is discovered which is the cause of the majority of transfusion reactions. 22

23 SWiTCH SWiTCH was a phase 3 trial that compared standard therapy ( TXN, Chelation) to alternate therapy ( HU and phlebotomy) Non inferiority trial with end point allowing for increased risk of stroke but requiring superior removal of Fe Inclusion criteria SCA, stroke, >18 months on transfusion, Fe Overload 133 children were randomized at 26 US sites 2 arms ( transfusions/chelation or Hydroxyurea and phlebotomy). Trial stopped d/t documented no difference in LIC between the 2 treatment arms and when 7 strokes occurred in the HU/ Phlebotomy arm 23

24 24 Twitching to Switch Ware, R. ASH Clinical News December 2015 TWiTCH Hydroxyurea as an Alternative to Transfusions for Stroke Prevention in Children with Sickle Cell Anemia Researchers randomized patients to receive either monthly transfusions (n=61) or daily Hydroxyurea (n=60) for 24 months( The HU group were given TXN until they were on a stable MTD of HU TCD were checked q 12 weeks, the TXN group kept sickle HGb <30% At the end TCD velocities were similar in both groups, indicating a similar risk and meeting criteria of non-inferiority In terms of safety, there were no deaths or new strokes, though there were 29 new neurologic events, including six transient ischemic attacks (3 in each arm).

25 Hydroxyurea Increases hemoglobin, decreases WBC Reduces hospitalizations by 50% Reduces hospital duration by 50% 25

26 Hydroxyurea Makes lower Hb S% in red cells by increasing MCV and producing HbF. MCV goes from 85 to 120 if dose is pushed to maximum tolerated. Hb can go from 8.5 to over 10 g/dl. It is safe if properly monitored RelaIvely inexpensive Well tolerated once a day medicaion Reduces mortality in adults by 40% Every SS or Sβ 0 thal pa;ent should be on HU

27 Impact of hydroxyurea on clinical events in the BABY HUG trial One hundred and ninety-three subjects 9-18 months were randomized to hydroxyurea (20 mg/kg/d) or placebo; Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain, dactylitis, acute chest syndrome, and hospitalization; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea. Blood 2012 Nov 22;120(22):

28 References Abbas, H., Kahale, M et al (2013). A review of acute chest syndrome in pediatric sickle cell disease. Pediatric Annals 42 (3) : Anderson, N. (2006) Hydroxyurea Therapy: Improving Lives of Patients with Sickle Cell Disease. Pediatric Nursing, 32(6), Ballas, S., Gupta, K., and Adams-Graves, P. (2012). Sickle Cell Pain: A Critical Reappraisal. Blood; 120 (18): Bernaudin, F., Verlhac, S. et al. (2011). Impact of early transcranial Doppler screening and intensive therapy on cerebral vaculopathy outcome in a newborn sickle cell cohort. Blood; 117 (4): Charache, S., Terrin, M., Moore, R., Dover, G., barton, F., Eckert, S., et al. (1995). Effect of hydroxyurea on the frequency of painful crisis in sickle cell anemia. The New England Journal of Medicine, 332,

29 References DeBaun, M., Armstrong, D. et al. (2012). Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia. Blood. 119(20): Driscoll, M. (2007). Sickle Cell Disease. Pediatrics in Review 28(7): Hulbert, M. McKinstry, R., et al (2011). Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease. Blood; 117 (3): Lemanek, K., Ranalli, M., Lukens, C. (2009). A Randomized Controlled Trial of Massage Therapy in Children with Sickle Cell Disease. Journal of Pediatric Psychology; 34(10): Lorey, F, Arnopp, J., and Cunningham, G. (1996) Distribution of Hemoglobinopathy Variants by Ethnicity in a Multiethnic State. Genetic Epidemiology. 13: Miller, A., and Gladwin, M. (2012). Pulmonary Complications of Sickle Cell Disease. Am J Respir Crit Care Med, 185(11):

30 References Platt, OS et al (1994) Mortality in Sickle Cell Disease. Life expectancy and risk factors for early death. N Eng J Med. 330: Powars, D.,Chan, L et al (2005) Outcome of Sickle Cell Anemia: A 4- Decade Observational Study of 1056 Patients. Medicine, 84(6): Rees, D., Williams, T., and Gladwin, M. (2010). Sickle Cell Disease. The Lancet. 376: Sibinga, E., Shindell, D., Casella, J., Duggan, A., and Wilson, M. (2006). Pediatric Patients with Sickle Cell Disease: Use of Complementary and Alternative Therapies. The Journal of Alterative and Complementary Medicine; 12(3): Smiers, F et al. (2010). Hematopoietic Stem Cell Transplantation for Hemoglobinopatheis: Current Practice and Emerging Trends. Pediatr Clin N Am; 57: