2. Objectives
• How to Care for Patients with SCD in the Community
Care Setting
• To know common acute and chronic complications of
SCD and how to treat them
• To know the protocol for initiation of hydroxyurea
therapy in patients with sickle cell disease
• To know recommendations for acute transfusion in
patients with sickle cell disease
4. Introduction
Sickle Cell Disease is a genetic disorder that results
in the formation of sickled red blood cells (RBCs).
Hemoglobin S (HbS) is an abnormal hemoglobin
that results from the substitution of a valine for
glutamic acid as the sixth amino acid of the beta
globin chain.
homozygous for sickle hemoglobin (HbSS, also
called sickle cell anemia [SCA])
One sickle hemoglobin gene plus a gene for
another abnormal hemoglobin type (e.g., HbSβ+-
thalassemia, HbSC).
5. Introduction
Deoxygenated RBCs ------→ HbS develop a sickle or
crescent shape ------→ inflexible ------- → increase
blood viscosity -------→ block or limit blood flow
within limbs or organs.
Aggravated ----- → abnormal interactions of these
RBCs with leukocytes, platelets, vascular
endothelium, and clotting factors---- → acute and
chronic complications.
6. Introduction
ConditionHbFHbCHbSHbA2HbA
Normal< 1002.595 to 98
Sickle cell trait< 2035 to 45< 3.550 to 60
Sickle cell anemia2 to 15085 to 95< 3.50
Sickle-HbC disease1 to 845 to 5045 to 50< 3.50
Sickle-beta ( + )
thalassemia
2 to 10065 to 90> 3.55 to 30
Sickle-beta ( 0 )
thalassemia
2 to 15080 to 92> 3.50
Beta thalassemia
minor
1 to 300> 3.590 to 95
8. Introduction
The baseline complete blood count (CBC) and peripheral blood
smear in individuals with SCD typically shows the following
findings :
●Hemoglobin level : 8 to 10 g/dL
●Hematocrit : 20 to 30 percent
●Polychromasia and reticulocytosis (typical reticulocyte count
approximately 3 to 15 percent)
●Sickled cells
●Howell Jolly bodies (nuclear remnants that have not been
phagocytosed, due to reduced splenic function)
●Mildly increased white blood cell (WBC) count in some cases
9. Caring for Patients with SCD in the Community
Care Setting
SCREENING, PREVENTION, AND
IMMUNIZATIONS
10. 1- Children with SCA are at increased risk of invasive
pneumococcal disease.
Prevention of invasive pneumococcal disease
Therefore, in addition to the recommended pneumococcal
vaccinations for all infants and children, those with SCA
should receive prophylactic oral penicillin (125 mg twice
daily for children younger than three years; 250 mg twice
daily for those three years and older) once the diagnosis is
established; this regimen should be continued until at least
five years of age.
SCREENING, PREVENTION, AND IMMUNIZATIONS
11. Prevention of invasive pneumococcal disease
Ensure that all persons with SCD have been vaccinated against
Streptococcus pneumoniae. (SOR: strong, based on
moderate-quality evidence)
Ensure that children 6 to 18 years of age who have functional
or anatomic asplenia have received at least 1 dose of 13-
valent pneumococcal conjugate vaccine. (SOR: adapted
from the Advisory Committee onImmunization Practices)
SCREENING, PREVENTION, AND IMMUNIZATIONS
12. SCREENING, PREVENTION, AND IMMUNIZATIONS
• Vaccines for patients with sickle cell disease
1- In patients six months and older, influenza vaccine should be
given annually. ( C )
2- The 7-valent pneumococcal conjugate vaccine (Prevnar)
should be administered as for children without sickle cell
disease. ( B )
3- The 23-valent polysaccharide pneumococcal vaccine should
be administered if two years or older, with another dose at
three to five years (if patient is 10 years or younger) or five
years (if patient is older than 10 years) after the first dose. ( B )
4- Meningococcal vaccine is recommended for patients two
years and older with sickle cell disease. ( C )
14. 2- Persons with SCD are also at increased risk of vascular
complications, particularly stroke.
All persons with SCA should be screened annually with
transcranial Doppler ultrasonography (TCD) beginning at
two years of age and continuing until at least 16 years of
age.
A TCD ≥ 200 cm per second : correlates with a 10% annual
increase in stroke risk.
When TCD findings are marginal or conditional (170 to 199 cm
per second) or elevated (200 cm per second or greater), the
child is considered a candidate for blood transfusion
therapy to prevent stroke and should be referred for
comanagement with a subspecialist.
SCREENING, PREVENTION, AND IMMUNIZATIONS
15. Screening for ischemic retinopathy
• Refer patients with SCD to an ophthalmologist for an annual
dilated retinal examination beginning at 10 years of age. (SOR:
strong, based on low-quality evidence)
• Rescreen persons with normal dilated retinal examination
findings at 1- to 2-year intervals. (SOR: consensus)
Screening for renal disease
• Begin annual screening of persons with SCD for
microalbuminuria and proteinuria with spot urine testing by 10
years of age. (SOR: consensus)
• Refer persons with proteinuria (> 300 mg per 24 hours) to a
nephrologist for further evaluation. (SOR: strong, based on low-
quality evidence)
SCREENING, PREVENTION, AND IMMUNIZATIONS
16. 3- In women with SCD, regular use of contraception can
decrease the health risks associated with an unintended
pregnancy.
Progestin-only contraceptives (pills, injections, and
implants) and barrier methods have no restrictions or
concerns for use in women with SCD.
The levonorgestrel-releasing intrauterine system is also
associated with few risks, except for those associated
with the device placement.
Pregnancy in women with SCD is associated with preterm
delivery, preeclampsia, stillbirth, high maternal
mortality, and severe fetal anemia.
SCREENING, PREVENTION, AND IMMUNIZATIONS
19. Vasoocclusive crisis (VOC)
Sudden onset of severe pain, often localized to the
extremities, chest, or back, but with few objective findings.
Pain episodes can begin as early as six months of age (when
it presents as dactylitis ) and typically last throughout life
(one-third had experienced pain by the age of one year,
two-thirds by the age of two years, and over 90 percent by
the age of six years )
Triggers for pain such as cold, wind, low humidity,
dehydration, stress, alcohol, and menses.
Recurrences have variable presentations and frequency.
VOC is a clinical diagnosis with no objective diagnostic tests.
20. Primary management of VOC includes rapid triage,
assessment, and administration of appropriate analgesics.
For mild or moderate pain, treatment may begin with
nonsteroidal anti-inflammatory drugs, if they are not
contraindicated.
For more severe pain, opioids are the first-line therapy.
Meperidine (Demerol) should not be used unless it is the
only effective alternative available.
Hydration and other nonpharmacologic therapies (e.g.,
maintaining body temperature) may also be useful.
Vasoocclusive crisis (VOC)
22. Acute chest syndrome (ACS)
Acute chest syndrome defined as the presence of a new lung
infiltrate in a patient with acute onset of lower respiratory
symptoms such as cough and shortness of breath, is less
common than VOC but potentially life threatening.
In children, it often presents with fever and signs of middle lobe
lung involvement, whereas adults are often afebrile and have
multilobe infiltrates.
ACS requires prompt evaluation and, once diagnosed, early
intervention with antibiotic therapy* and hospitalization.
For mild episodes of ACS we suggest the use of simple
transfusion ( target Hb ?? ) , while for moderate to severe ACS
we suggest the use of exchange transfusion
* (Third generation cephalosporin and a macrolide or a fourth generation fluoroquinolone )
23. Fever
-- Fever greater than 101°F (38.3°C), even in the absence of other
signs of infection, should be evaluated carefully ( high risk of
overwhelming bacterial infections or sepsis ).
Should be treated empirically until culture results are available
24. Hepatobiliary tract complications
-- Hepatobiliary tract complications (e.g., cholelithiasis,
acute cholecystitis, biliary sludge, acute
choledocholithiasis) are common in persons with SCD,
particularly in those with SCA.
Gallstones occur in up to 75% of adults with SCD and,
when asymptomatic, should be managed with
watchful waiting.
25. Priapism
Prolonged episodes may lead to irreversible changes including
tissue necrosis, fibrosis, and erectile dysfunction.
Administer aggressive oral or intravenous hydration and oral or
intravenous analgesia for episodes of priapism lasting 4 hours
or longer. (SOR: strong, based on low-quality evidence)
Consult with a urologist for an episode of priapism lasting 4 hours
or longer. (SOR: consensus)
Aspiration of blood from the corpus cavernosum for individuals
with SCD and an episode of low flow priapism lasting more
than four hours or exchange transfusion for cases of priapism
that are refractory to aspiration .
26. Aplastic crisis
Aplastic crisis is characterized by an acute drop in hemoglobin
level and a markedly reduced number of reticulocytes in the
peripheral blood (typically, reticulocytes <1.0 percent,
absolute reticulocyte count <10,000 per microL).
Most cases in children follow infection with human parvovirus
B19
Other reported causes of transient aplasia are infections by
Streptococcus pneumoniae, Salmonella, other streptococci,
and Epstein-Barr virus.
Aplastic crisis can result in a rapid and life-threatening drop in
hemoglobin level caused by chronic hemolysis without the
ability of the bone marrow to compensate.
Management is with transfusion.
27. Splenic sequestration crisis
Splenic sequestration crisis is characterized by an acute drop in
hemoglobin level caused by vasoocclusion within the spleen
and splenic pooling of RBCs.
A large percentage of the total blood volume can become
sequestered in the spleen, leading to hypovolemic shock and
death.
Patients with splenic sequestration crisis present with a rapidly
enlarging spleen and a marked decrease in hemoglobin level
despite persistent reticulocytosis
Up to half of individuals who survive a splenic sequestration crisis
are reported to have recurrent sequestration, and
splenectomy is often used after the first acute event to
prevent recurrence.
30. Hydroxyurea
Hydroxyurea therapy decreases SCD-related complications but is
currently underused.
Hydroxyurea works primarily by increasing the level of fetal
hemoglobin (HbF), which does not sickle.
This improves several clinical outcomes, such as decreasing the
frequency of VOCs and ACS, reducing mortality, and
decreasing the need for RBC transfusions and
hospitalizations.
Hydroxyurea is rapidly absorbed, has nearly complete
bioavailability, and requires only once-daily oral dosing.
32. Protocol for Initiation of Hydroxyurea Therapy in Patients with
Sickle Cell Disease
Laboratory tests (recommended before starting therapy )
CBC with WBC differential, reticulocyte count, platelet count,
and RBC MCV
Comprehensive metabolic profile, including kidney and liver
function tests
Pregnancy test for women
Quantitative measurement of HbF, if available (e.g.,
hemoglobin electrophoresis, high-performance liquid
chromatography)
33. Protocol for Initiation of Hydroxyurea Therapy in Patients with
Sickle Cell Disease
Initiating and monitoring therapy
Counseled about the need for contraception while taking
hydroxyurea
Starting dosage for adults: 15 mg per kg per day (round up to the
nearest 500 mg); 5 to 10 mg per kg per day in patients with chronic
kidney disease
Starting dosage for infants and children: 20 mg per kg per day
Monitor CBC with WBC differential and reticulocyte count at least
every 4 weeks when adjusting dosage
Aim for a target absolute neutrophil count ≥ 2,000 per μL (2.0 × 109
per L); younger patients with lower baseline counts may safely
tolerate absolute neutrophil counts as low as 1,205 per μL (1.2 × 109
per L)
Maintain platelet count ≥ 80,000 per μL (80.0 × 109 per L)
34. Protocol for Initiation of Hydroxyurea Therapy in Patients with Sickle Cell
Disease
If neutropenia or thrombocytopenia occurs:
Maintain hydroxyurea dosing
Monitor CBC with WBC differential weekly
When blood counts have recovered, reinstitute hydroxyurea at a dosage of
5 mg per kg per day lower than the dosage given before onset of cytopenia
If dose escalation is warranted based on clinical and laboratory findings:
Increase in increments of 5 mg per kg per day every 8 weeks
Give until mild myelosuppression is achieved (absolute neutrophil count
2,000 to 4,000 per μL [2.0 × 109 to 4.0 × 109 per L]), up to a maximum of 35
mg per kg per day
Once a stable dosage is established, laboratory monitoring should include CBC
with WBC differential, reticulocyte count, and platelet count every 2 to 3
months
35. Protocol for Initiation of Hydroxyurea Therapy in Patients with
Sickle Cell Disease
A clinical response to treatment may take 3 to 6 months;
therefore, a 6-month trial at the maximum tolerated dose is
required before considering discontinuation because of lack
of adherence or nonresponse
Monitor RBC, MCV, and HbF levels for evidence of consistent
or progressive response
A lack of increase in MCV or HbF is not an indication to
discontinue therapy
Long-term hydroxyurea therapy is indicated in patients who
have a clinical response
Therapy should be continued during hospitalizations or illness
36. RBC transfusion
RBC transfusion, the first disease-modifying therapy used for
SCD, reduces the percentage of circulating RBCs with HbS,
thereby treating acute symptomatic anemia as well as
treating and preventing many SCD complications.
Episodic transfusion is used acutely in response to an SCD
complication or prophylactically in preparation for general
anesthesia and surgery.
Long-term transfusion therapy is used when sustained reduction
of HbS (e.g., to less than 30%) is desired for primary or
secondary prophylaxis for specific SCD complications, most
commonly stroke in children.
37. Recommendations for Acute Transfusion
in Patients with Sickle Cell Disease
• Indications for acute transfusion
For all adults (ie, those >18 years) with SCD who are admitted to the hospital for an acute medical condition, we recommend thromboprophylaxis with one of the following:
●One of the low molecular weight heparins (eg, enoxaparin, dalteparin, tinzaparin) at prophylactic doses
●Low dose unfractionated heparin (eg, 5000 units SQ three times a day)
●Fondaparinux (eg, 2.5 mg SQ daily)
For patients with SCD who have a radiologically confirmed acute ischemic stroke, we suggest transfusion (Grade 2C). The goal of transfusion is to lower the percentage of sickle hemoglobin to ≤30 percent of total hemoglobin and to aim for a total hemoglobin level of approximately, but not greater than, 10 g/dL. For most patients receiving transfusion, we suggest exchange transfusion rather than simple transfusion (Grade 2C). It is appropriate to provide simple transfusion while assembling resources for exchange transfusion.
If the patient is hypovolemic, normal saline (ie, 0.9 percent saline) is appropriate to maintain hemodynamic stability.
If the patient is euvolemic and receiving maintenance intravenous fluids, we use one-quarter or one-half normal saline with or without glucose.
●Home management is the most frequent setting for acute pain management in SCD. We use a stepwise approach to match therapies with pain severity (table 1 and figure 5). Patients not receiving chronic opioids start with non-opioid therapy for mild pain (table 2) followed by opioids of escalating strengths (table 3). Individuals who require long-acting opioids on a regular basis should have additional short-acting medication for breakthrough pain. There should be a clear plan for when to seek medical services and whom to contact if these do not provide adequate pain relief. (See 'Management at home' above.)
●Most patients with SCD-associated pain only present to the hospital or emergency department (ED) when their pain has exceeded what they can manage at home with oral opioids. Acute pain should be treated as an Emergency Severity Index (ESI) of 2 (<30-minute triage wait time) with rapid reassessment after initial opioid dosing (figure 1). Appropriate agents include intravenous morphine (0.1 to 0.15 mg/kg), hydromorphone (0.02 to 0.05 mg/kg), or fentanyl (for patients with renal or hepatic dysfunction). If pain is not relieved with more than two doses, hospitalization for round-the-clock parenteral analgesics is indicated, preferably using a patient-controlled analgesia (PCA) program that allows additional demand dosing. Attention should be paid to breakthrough pain, hydration status, and potential opioid complications
Specific therapies for ACS include the following:
•For mild episodes of ACS we suggest the use of simple transfusion, while for moderate to severe ACS we suggest the use of exchange transfusion (Grade 2C). The final target hemoglobin should be no higher than 10 g/dL. Regardless of ACS severity, we recommend simple transfusion in all patients with a hemoglobin <5 g/dL, as a hemoglobin S percentage close to 30 percent can be achieved by simple transfusion alone (Grade 1B). (See 'Transfusion' above.)
•As pneumonia cannot be reliably distinguished from ACS, we recommend prompt initiation of antibiotics in all patients with ACS (Grade 1B). Our preference is to employ a third generation cephalosporin and a macrolide or a fourth generation fluoroquinolone.
●As ACS is an acute medical condition, we recommend thromboprophylaxis in all adults with SCD admitted to the hospital for ACS (Grade 1B). Our preference is to administer a once daily prophylactic dose of low molecular weight heparin or fondaparinux. (See "Overview of the management and prognosis of sickle cell disease", section on 'Thromboembolism prophylaxis' and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)
●For prevention of ACS recurrence as well as overall reduction in mortality, we recommend that hydroxyurea be administered to all adults with a history of ACS unless otherwise contraindicated (ie, renal failure) (Grade 1B). (See 'Hydroxyurea' above.)
●In patients who have two or more episodes of moderate to very severe ACS episodes in a 24-month period despite maximal hydroxyurea therapy, we suggest a chronic transfusion program to maintain a hemoglobin S percentage <50 percent (Grade 2C). (See 'ACS severity index' above.)
Bacteremia – Encapsulated organisms, especially Streptococcus pneumoniae and Haemophilus influenzae [26-33]. Other common organisms include Escherichia coli, Staphylococcus aureus, and Salmonella species
Meningitis – Encapsulated organisms, especially S. pneumoniae. H. influenzae is also seen but has become less common following institution of the vaccine.
Pneumonia/ACS – Mycoplasma pneumoniae, Chlamydia pneumoniae (which together account for about 20 percent of cases), and Legionella.
For empiric parenteral antibiotics, the following regimen is most commonly used in the United States:
•Parenteral ceftriaxone as a single dose of 50 to 75 mg/kg, (maximum dose 2 g), the dose of which is increased (dose 75 to 100 mg/kg, maximum dose 2 g) in regions with a high prevalence of antibiotic resistant S. pneumoniae.
•In patients who are hemodynamically unstable or suspected to have meningitis, vancomycin is added (dose 15 mg/kg IV, maximum dose 1 g).
•For patients who are allergic to cephalosporins, clindamycin can be used (dose of 10 to 15 mg/kg, maximum dose 1.6 g). Most patients requiring this therapy should be admitted for observation due to the shorter half-life of this antibiotic.
Priapism — Priapism (unwanted erection lasting more than two to four hours) is a common, serious, and often underdiagnosed problem in SCD. Prolonged episodes may lead to irreversible changes including tissue necrosis, fibrosis, and erectile dysfunction.
We recommend the use of aspiration of blood from the corpus cavernosum followed by saline irrigation and instillation of adrenergic agonists as initial treatment for individuals with SCD and an episode of low flow priapism lasting more than four hours (Grade 1C).
In cases of priapism that are refractory to aspiration and instillation, we suggest prompt initiation of exchange transfusion. Erythrocytapheresis is the preferred modality, and the post-transfusion hemoglobin should not exceed 10 g/dL.
In children older than 18 to 24 months of age and adults with sickle cell disease (SCD) who have frequent painful episodes, severe symptomatic anemia, or a history of acute chest syndrome or other severe vasoocclusive events, we recommend treatment with hydroxyurea (Grade 1A). This agent should be used for six months to determine if it is providing a clinical benefit, and continued for as long as it is tolerated and effective.
The recommended initial oral dose of hydroxyurea for children and adults with a creatinine clearance >60 mL/min is 10 to 15 mg/kg per day. Subsequent dose increments are determined by the patient's response. (See 'Dosing' above.)
•We suggest that all very young children (ie, 9 to 18 months of age) with SCD, independent of disease severity, be treated with hydroxyurea (dose: 15 mg/kg per day) (Grade 2A). Compounding pharmacy support is required until a liquid formulation of hydroxyurea becomes commercially available. (See 'Very young children and the BABY HUG trial' above.)
•There is no information on the safety and efficacy of hydroxyurea in children younger than nine months of age. However, given the high prevalence of splenic damage prior to nine months of age, we suggest the use of hydroxyurea in children younger than nine months of age with symptomatic disease (Grade 2C). (See "Overview of the clinical manifestations of sickle cell disease", section on 'Infection'.)
•In children who have been started on hydroxyurea who remain asymptomatic or minimally symptomatic, while awaiting additional data, we suggest continuing hydroxyurea indefinitely, with close monitoring as outlined below (Grade 2B)