Sickle cell disease (SCD) is a group of inherited blood disorders caused by an abnormal hemoglobin- hemoglobin S (HbS). HbS results from point mutation in the B –globin genes, resulting in the substitution of valine for glutamic acid at position 6 of the B-globin chains. SCA (HBSS) is the most common and most severe form An estimate of over 300,000 babies annually are born globally with SCD and 80% are from sub-Saharan Africa (SSA) In Uganda, 20,000 babies are born with SCA annually, and its estimated that 80% die before their fifth birthday .

1. Comprehensive Care for persons with Sickle cell
Disease
Dr. Wanyama Ronald Stephen, MBCHB
Kampala international university

2. Outline
• Pathophysiology of SCD .
• Comprehensive care for SCD
Management of acute complications
• Hydroxyurea use in patients with SCD

3. Background – SCD Epidemiology
• Sickle cell disease (SCD) is a group of inherited blood disorders caused by an
abnormal hemoglobin- hemoglobin S (HbS).
• HbS results from point mutation in the B –globin genes, resulting in the
substitution of valine for glutamic acid at position 6 of the B-globin chains. SCA
(HBSS) is the most common and most severe form
• An estimate of over 300,000 babies annually are born globally with SCD and
80% are from sub-Saharan Africa (SSA)
• In Uganda, 20,000 babies are born with SCA annually, and its estimated that
80% die before their fifth birthday .

4. Back Ground – SCD Pathophysiology
Upon deoxygenation, the HbS molecule
polymerizes within the RBC leading to
shape changes
Sickled RBC are rigid and adhesive, so obstruct
small blood vessels and lead to tissue
ischemia
Vaso-occlusion is a complex event, involving
WBC, reticulocytes, sickled cells, and
endothelium
Hemolysis and endothelial vasculopathy also
contribute to organ dysfunction
SCD can affect every system in the body and
causes progressive organ damage

5. Comprehensive care for SCD improves
outcomes
• Comprehensive care for SCD involves the prevention, screening for
and treating of SCD associated complications across the life span

6. Care for children and adults with SCD
Health Maintenance
for SCD
1. Education
2.Penicillin and malaria
prophylaxis
3.Immunisation
4. Screening for chronic
complication
Treatment of acute
and chronic
complications
1. Pain management
2. ACS
3.Treatment of fever
Disease Modifying
Treatments
1.Hydroxyurea
2. Chronic blood
transfusion
3. L. Glutamine
4.Voxelotor
Cure
Bone marrow
Transplant
Gene therapy

7. Education and Counselling : Patients and care
givers
• Inheritance patterns of SCD
• Complications of SCD
• Educate – ask patients to seek care for all fevers above 38.50C
• Teach parents how to palpate for the spleen especially . in infants and
younger children with SCD

8. Prophylaxis against infections
Penicillin prophylaxis
Penicillin v125mg <3 years and 250mg for those 3 -5 years twice daily
Don’t discontinue at 5 years if child had a splenectomy
Malaria chemoprophylaxis
Immunization: Receive all vaccines according to local immunization schedule
• Infants receive the complete 3 does of PCV vaccinations
• Additional dose of PCV 23 at ages 2 t and 5 years old

9. Nutritional Supplements
Micronutrient deficiencies are common in
children with SCD
Persons with SCD may experience higher
metabolic rates than non SCD controls
Role of routine micronutrient
supplementation not well studied
Recommendation is replace deficient
micronutrient
Routine folic acid (5mg/daily) given as local
standard of care

10. Primary Stroke prevention
• Annual Transcranial Doppler Ultra sound
Scan(TCD) from ages 2-16 years
• Abnormal TCD (>200cm/sec):chronic
blond transfusion if feasible or start
hydroxyurea
• Conditional, 170-199 cm/sec, repeat in 6
months
Screen for Stroke

11. Screening for renal disease
• Screen all children >10 years
annually for proteinuria
• If result is positive, do early
morning urine albumin
creatinine ratio and if abnormal
refer to a nephrologist
• Repeat annually for negative
result

12. Screening for pulmonary disease
• Using history and physical
examination, screen children
and adults for Asthma, COPD
• If suggestive do further
assessment with pulmonary
tests
• Routine pulmonary function
tests not recommend
• Routine screening for pulmonary
hypertension in asymptomatic
children and adults not
recommend

13. Reproductive counselling for patients with
SCD
• Counsel men and women with SCD to have a reproductive plan
• Offer contraception to avoid unintended pregnancy
• Educate need for testing partners of persons with SCD for
haemoglobinopathies
• Pregnancy is in SCD high risk – have clear follow up plan
• Stop hydroxyurea 3 months before a woman gets pregnant

14. Treatment of Acute and Chronic Complications
Acute complications
• Pain crises
• Acute chest syndrome
• Severe acute anaemia
• Fever
• Priapism
• Acute stroke
• Acute splenic sequestration
Chronic complications
• Leg ulcers
• Avascular necrosis
• Stroke
• Recurrent priapism
• Chronic kidney disease
• Pulmonary hypertension
• Chronic lung disease

15. Evaluation of pain in SCD
• Patients who present in pain must be evaluated rapidly – both for pain and
any underlying comorbidities
• Evaluate for severity which can vary from mild to debilitating
• Do not delay initiation of analgesia – Start within 20 minutes

16. Home Management of pain is the most
common type of management in SCD
• Evidence from the PiSCES trial – used patient dairies
• Home management includes access to analgesia and instructions
when to seek medical attention
• Mild pain – Paracetamol or NSAIDS . May escalate to opioids for some
un resolving pain
• Adjuvant therapies: Relaxing, mild exercise, hot compress. Avoid – cold
/ice compression which can precipitate sickling
• Seek medical care : Fever, cough, signs of stroke, splenic sequestration

17. Hospital Management of Pain
• Majority of patients have true, severe pain and do not have drug seeking
behavior
• Assess pain: location and severity of pain
• Patient or parental report –most important assessment tool for pain
• Use pain scores for older children; younger children- degree of irritability
• Assess for contributing comorbidities – ACS, stroke, infection . These may
develop during hospitalization – assess vitals including pulse oximetry

18. Pain score cards

19. Management of Acute Pain Episodes: MHSCC
Protocol
• Assess patient’s general state, the level of consciousness and
hydration.
• Vitals and examine areas of tenderness
• Evaluate the severity
• Look for other causes of pain other than VOC
• Rapidly assess the patient’s recent use of analgesics

22. Management of Acute pain: Pharmacological
Iv morphine may be used at 0.1-0.15mg/kg – max dose 10mg

23. Adjuvant Treatments
• In euvolemic patients, administer fluids at maintenance. Total fluid should
not exceed 1.5 times the maintenance
• To reduce the risk of ACS, initiate use of incentive spirometry
• Do not transfuse children with VOC unless there are other indications for
blood transfusion such ACS.
• A painful crisis without fever does not require antibiotics.
• Heat compresses :avoid cold/ice compresses
• Early ambulation

24. • Reassess patient pain control at least every 4 hours
• Readjust /escalate doses doses if necessary (mind time to peak to
avoid toxicity)
• NSAIDS for hospitalized patients should be minimized (5 to 7 days)
• Avoid PRN medications
• Review prior analgesia dosing to guide initial dosing
• Treatment of respiratory depression due to morphine overdose
• Naloxone (0.01 mg/kg/dose, max 0.4 mg/dose) IV every 2-3 minutes
as necessary to a maximum of 10 doses

25. Newer Treatments for Acute Pain
• Patient controlled analgesia(PCA) have been found very effective
• Intranasal fentanyl also effective for acute pain management
• Ketamine may be used for pain refractory to opioids (intranasal or
continuous infusion)
• Offer psychosocial support and disease modifying agents like
hydroxyurea

26. When its more than pain
• Abdominal pain with distension – Liver /splenic sequestration
• Severe pain with increasing hematuria may indicate renal pathology
• Pain with leukopenia, may indicate infection
• Pain with worsening anemia may indicate bone marrow suppression

27. Role of Hydroxyurea in the treatment of
SCD
• Hydroxylated analog of urea originally synthesized in 1869
• First animal studies in 1928 for leukopenia, macrocytosis, anemia, death
• First tested in SCD in 1984
• Principal mechanism of cytotoxicity is the inhibition of DNA synthesis
(Ribonucloetide Reductase inhibitor)- causing intermittent suppression of
erythroid progenitors
• Spontaneous recovery of the enzyme occurs when hydroxyurea is
removed
• Resistance and tolerance have not been described to occur

28. Hydroxyurea: Multiple Mechanisms of
Action with Multiple Benefits to Patient
• HbF induction
• Myelosuppression
• ↓RBC adhesion to
endothelium
• Better rheology
• ↑ Nitric Oxide

29. Hydroxyurea is Efficacious in Children and
Adolescents with SCD
• Reduces Pain episodes by 50%
• Reduces need for blood transfusion
• Decreases trans cranial doppler velocities ,reduces risk of primary and
secondary stroke
• Decreases the rates of acute chest syndrome
• Reduces rates of hospitalization
• Preserves splenic function in infants and improves growth and development
Opoka et al, Ware et al, Jayabose et al, wang et al.

30. Thirty Years of Research

31. Hydroxyurea is Safe and Does not
Increase Malaria Risk in African Children

32. Indications and Contraindications for
Hydroxyurea Use
• Frequent Pain Crises ,>5 in a
year
• Stroke or history of stroke
• Abnormal TCD velocities>
200cm/sec
• Low baseline
Haemoglobin,<6g/dL
• History of/admission for acute
chest syndrome
Contraindications
• Pregnancy or sexually active
and not willing to use
contraception
• Active liver disease
• Hypersensitivity to
Hydroxyurea
• Significant non compliance to
therapy

33. • Offer Hydroxyurea to all children older than 9 months – National
Heart, Lung and Blood Institute

34. Dosing and Monitoring
• Baseline Investigations
• CBC with differential ,MCV and reticulocyte count
• Quantitative HB electrophoresis – Help in monitoring response
• Creatinine and Urea – Should be in normal range
• Liver function – AST/ALT- Should be <2 times the upper limit

35. Prior to Initiating Hydroxyurea Therapy
• Complete history and physical exam.
• Discuss the rationale and potential adverse effects of hydroxyurea
with patient and family members.
• Document that family agrees to have regular clinic monitoring.
• Document diagnosis of SCD
• Patient must meet initial blood count and chemistry criteria: ANC
> 1,500/µl, platelet > 100,000/ul, and ALT< X2 the upper limit of
normal, and normal creatinine .

36. Dosing and Monitoring
• Start at 20mg/kg /day for children, 15mg/kg /day for adults
• Monitor CBC every month for 3 months, then every 3 months
• Monitor for toxicity and clinical and laboratory response
• Escalate when indicated: Abnormal TCD, stroke, ANC>6,000,
no clinical response
• Escalate by 5mg/kg/day every 6-8 weeks up to 30mg/kg/day

37. Hydroxyurea at MTD is Safe and Superior to Fixed Dose

38. Laboratory Effects of MTD vs. Fixed
Dose
Adapted from Opoka et al

39. • MTD: Mild myelosuppression- ANC 2-4,000/uL without toxicity
• Monitor CBC at each dose escalation
• At each monitoring visit, assess
• Interim clinical events
• Adherence; check MCV, WBC, ANC, ARC on CBC which should reduce while
haemoglobin level should increase
• Reweigh the patient and check dose against weight
• CBC: Stop Hydroxyurea if ANC <1500 OR Hb<6 AND ARC <80,000 OR platelets
<80,000
Dosing and Monitoring

40. Dosing and Monitoring
• Monitor WBC weekly after holding hydroxyurea. Restart at a dose
5mg/kg/day lower when counts recover
• Effectiveness of hydroxyurea depends on adherence .
• Clinical response may take 3- 6 months
• Lack of increase in HBF or MCV is not an indication to stop therapy
• Do not discontinue therapy due to uncomplicated fever or
hospitalization

41. Challenges with Hydroxyurea therapy in
Clinical Practice
• 1. Formulations of 250 and 500 mg capsules
• 2. Capsule formulations and no syrups
• 3.Adherence to dosing
• 4.Erractic availability of drugs

42. Fertility and Hydroxyurea
• SCD is associated with fertility
challenges , especially among
males
• Some studies in rats revealed
reduction in sperm counts and
motility following hydroxyurea
exposure
• Similar trends suggested by
other studies post pubertal
males

43. THANK YOU
Q & A