Disclosure info CHILDREN WITH SICKLE CELL DISEASE (SCD): MANAGEMENT AND TREATMENT

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.