Sickle Cell Disease

Overview

Sickle cell disease (SCD) is a group of inherited disorders that results from a genetic mutation in the beta-globin gene forming sickle hemoglobin, Hb S. Hb S polymerizes under deoxygenated conditions in red blood cells giving them an abnormal “sickle” shape.

Amino Acid Sequence Ultimately Causing Sickle Cells

Sickle cell disease results in chronic hemolytic anemia, systemic inflammation, small vessel vaso-occlusion, and endothelial cell dysfunction. Nearly every organ system in the body can be affected. Acute complications include painful vaso-occlusive crises, acute chest syndrome, and stroke. Chronically, sickle cell disease can lead to end organ damage in the brain, heart, lungs, and kidneys.

Other Names & Coding

Hb S disease
Hemoglobin S disease
SCD (acronym)
Sickle cell disorders (a broad group of conditions that includes sickle cell anemia)

The convention for indicating the composition of hemoglobin types in the red cells of an individual is to use an acronym listing the types in decreasing proportion or amount. For example, sickle cell carrier (sickle cell trait), in which the amount of HB F (fetal) is greater than that of Hb A (adult), which is greater than that of Hb S (sickle), is designated as FAS.

ICD-10 coding

D57.0x, Hb SS disease with crisis

D57.1, Sickle cell disease without crisis

D57.2xx, Sickle cell/Hb-C disease

D57.4xx, Sickle cell thalassemia

D57.8xx, Other sickle cell disorders

An "x" indicates the need or potential for additional digits to provide a more specific diagnosis. More coding details can be found at ICD-10 for Sickle Cell Disorders (icd10data.com).

Prevalence

Sickle cell disease is the most common abnormality found in newborn screening programs. The incidence in African Americans of sickle trait is 1:14; sickle cell anemia is 1:396. [Lorey: 1996] The number of individuals with sickle cell disease in the United States may approach 100,000, even after accounting for the effect of early mortality on estimations. A paucity of high-quality data limits appropriate estimation. [Hassell: 2010]

Genetics

Normal hemoglobin is composed of 2 alpha subunits and 2 beta subunits. Abnormal sickle hemoglobin is formed from a single point mutation in the beta globin gene, HBB, which results in substitution of valine for glutamine at position 6 on the beta helix. Sickle cell disease is inherited in an autosomal recessive manner when patients have 2 abnormal beta globin genes and at least 1 of the beta globin mutations is Hb S. Hb S can also be inherited with other mutations such as Hb C (Glu6Lys) or beta thalassemia, which have a sickle phenotype. The term sickle cell anemia is reserved for patients who are homozygous for the Hb S mutation. Sickle Cell Disease (GeneReviews) offers additional information.

Prognosis

Several decades ago, the majority of individuals with sickle cell anemia died during childhood. However, with modern comprehensive care, newborn screening with early initiation of penicillin prophylaxis, improved immunizations, and use of hydroxyurea, children now live well into adulthood. The median life expectancy is 58 years for patients with Hb SS or sickle β0 thalassemia and 66 years for patients with Hb SC or sickle β+ thalassemia. [Elmariah: 2014]

Practice Guidelines

An expert panel convened by the National Heart, Lung, and Blood Institute published evidence-based guidelines in 2014 for the management of acute and chronic complications of sickle cell disease. A pdf of the full guidelines (161 pages) can be found at:

Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J.
Evidence-Based Management of Sickle Cell Disease: Expert Panel Report ( PDF Document

3.2 MB)
National Heart, Lung, and Blood Institute. 2014.

Summary guidelines (16 pages, subscription required) can be found at:

Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J.
Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members.
JAMA. 2014;312(10):1033-48. PubMed abstract

Roles of the Medical Home

For the child with sickle cell disease, the medical home should manage well-child care, including standard childhood immunizations, acute illnesses unrelated to sickle cell-disease, and chronic comorbid conditions, such as asthma. Sickle cell-specific care (e.g., trans-cranial Doppler (TCD) evaluation, hydroxyurea) should be managed by a pediatric hematologist with experience in sickle cell comprehensive care. In locations remote from sickle cell specialty care, the medical home may also provide care for acute complications of sickle cell disease (e.g., febrile illness and mild pain crises) and laboratory monitoring for hydroxyurea. Comprehensive sickle cell care is multidisciplinary and the medical home plays an important role in helping to coordinate this care. The Sickle Cell Disease National Resource Directory (CDC) lists national agencies, specialty care centers, and community-based organizations that provide services and resources for people affected by sickle cell disease.

Clinical Assessment

Overview

Sickle cell disease is a multisystem disorder that can cause acute and chronic complications in nearly every organ system. Careful history and physical examination should focus on eliciting signs and symptoms of these complications or comorbid conditions.

Pearls & Alerts for Assessment

Pulse oximetry can underestimate oxygen saturation

Pulse oximetry is an inaccurate measurement and often underestimates oxygen saturation due to increased levels of carboxyhemoglobin and methemoglobin in patients with sickle cell disease.

Assessment of pain

Children experiencing an acute vaso-occlusive pain crisis may not have changes in vital signs (tachycardia or hypertension). Assessment of pain should be based primarily on the patient’s subjective report.

Screening

For the Condition

Universal screening for sickle cell disease is conducted in all states as part of newborn screening programs. Hemoglobin separation techniques (e.g., isoelectric focusing, IEF) can identify infants with sickle trait (FAS), sickle cell disease or sickle β0 thalassemia (FS), sickle-Hb C (FSC), or sickle β+ thalassemia (FSA). If an abnormal newborn screen is obtained, repeat newborn screening should be sent in accordance with recommendations by the appropriate state newborn screening program. If the confirmatory testing is positive for homozygous sickle cell anemia or sickle β0 thalassemia, the patient should be referred to a pediatric hematologist with expertise in management of sickle cell disease and started on penicillin prophylaxis. Sickle Cell Disease provides additional information for response to a positive newborn screen.

Of Family Members

Parents and partners of a parent of a child with sickle cell disease who are unaware of their carrier status should be screened with a hemoglobin electrophoresis for sickle trait, Hb C, or beta thalassemia so that appropriate genetic counselling may be provided about risks to future offspring.

For Complications

Retinopathy: Annual to biennial screening for sickle retinopathy should be performed starting at age 10 years. Those with retinopathy should be referred to a retina specialist.

Stroke risk: Measurement of cerebral blood flow velocities by transcutaneous Doppler ultrasonography should be conducted by those trained in the technique specific for sickle cell disease. Begin annual testing at age 2 and until age 16 to screen for elevated stroke risk requiring intervention with chronic transfusion therapy.

Pulmonary hypertension: Routine screening echocardiograms are no longer recommended in asymptomatic individuals; however, those with symptoms or signs should be referred for an echocardiogram.

Iron overload: Patients receiving chronic transfusion therapy are at risk for iron overload and should have screening MRIs for liver iron content at least annually.

Presentations

Infants are usually identified by newborn screening during the asymptomatic period. Prior to the advent of universal newborn screening, patients with the severe sickle cell genotypes would present initially with dactylitis of the hands or feet, severe illness including splenic sequestration or sepsis, or sudden death. Patients with more mild genotypes (e.g., Hb SC or sickle beta+ thalassemia) might present with unexplained recurrent pain as older adolescents or adults.

The presentation of complications related to sickle cell disease depends on the organ system involved. Those with stroke will usually present acutely with a focal neurologic deficit, such as hemiparesis, aphasia or ataxia, depending on the anatomic location of the stroke. Depending on the severity or stage of sickle retinopathy, patients may present with spots in the field of vision (floaters), blurriness, decreased visual acuity, or visual field loss. Patients with pulmonary hypertension may present with exertional dyspnea or persistent hypoxia.

Diagnostic Criteria

Diagnosis is established by hemoglobin separation techniques, such as isoelectric focusing, high performance liquid chromatography, or hemoglobin electrophoresis.

Clinical Classification

Sickle cell disease is a group of sickling disorders. There are a variety of genotypes and associated clinical phenotypes. The most common genotypes are summarized in the table below.

Common Sickle Cell Genotypes

Differential Diagnosis

Differential diagnoses include:

Homozygous sickle cell anemia (Hb SS)
Sickle-Hb C disease
Sickle β0 thalassemia
Sickle β+ thalassemia
Sickle-Hb D disease
Sickle-Hb E disease
Other sickle syndromes

All of these are sickling syndromes that can manifest as hemolytic anemia with intermittent episodes of vaso-occlusion. These usually can be distinguished based on the hemoglobin separation results for diagnostic testing. Homozygous sickle cell anemia is the most severe clinical phenotype with more significant anemia and increased frequency of disease complications including vaso-occlusive pain crises. Patients with sickle beta0 thalassemia are clinically similar to homozygous Hb SS patients with the addition of microcytosis on laboratory evaluation. Hemoglobin C and sickle beta+ thalassemia have milder clinical phenotypes with higher baseline hemoglobins and less frequent complications. Co-inheritance with Hb D results in a severe phenotype similar to homozygous sickle cell anemia. Sickle-Hb E disease is usually seen in patients with some Asian ancestry (where Hb E is prevalent) and results in a mild phenotype similar to sickle beta+ thalassemia.

Comorbid & Secondary Conditions

Commonly co-occurring conditions may include:

Asthma: Patients with uncontrolled asthma may have more frequent vaso-occlusive pain due to increased sickling with hypoxia.
Sickle lung disease: Due to chronic sickling within the lung vasculature, patients develop obstructive, and then restrictive, changes in the lungs, which frequently leads to pulmonary hypertension and is the leading cause of death in adults with sickle cell disease.
Stroke: Children with prior stroke may have residual neurologic deficits.
Sickle nephropathy: Children with sickle cell disease can develop renal complications over time. This usually starts with urine concentrating defects (hyposthenuria) followed by glomerular hyperfiltration, proteinuria, and eventually focal segmental glomerulonephritis.
Retinopathy: If untreated, sickling within the retinal vessels can cause proliferative retinopathy, hemorrhage within the retina, retinal detachment, and blindness.
Osteonecrosis: Infarction of the bones can cause chronic severe pain and limitation in mobility.

History & Examination

Current & Past Medical History

It is important to understand the history of prior complications or other comorbid conditions. Knowledge of the frequency of vaso-occlusive crises and what medications work best for controlling pain can help with planning for treatment of future episodes. Patients with recurrent acute chest syndrome require additional long-term monitoring for development of chronic lung disease or pulmonary hypertension. Patients with a severe history of complications may need therapy with chronic transfusions or may qualify for bone marrow transplant.

Family History

Birth parents will have a sickle trait, Hb C trait, or beta thalassemia trait. Because universal newborn screening for this disease was not implemented prior to the last couple of decades, there may be history of family members who died during childhood, had frequent pain, stroke, or gallstones.

Pregnancy/Perinatal History

Pregnancy and birth history are usually normal since the predominant form of hemoglobin present in the fetus and newborn is unaffected fetal hemoglobin. It is possible if the parents were aware of their carrier status that chorionic villus sampling or amniocentesis was performed to establish prenatal diagnosis.

Developmental & Educational Progress

More than a quarter of children with sickle cell disease will experience a silent cerebral infarct by the age of 6 years. This number increases to 37% by 16 years of age. Silent cerebral infarcts are associated with decreased IQ and poor academic performance. [DeBaun: 2014] Referral to a sickle cell expert is recommended for those with silent infarct. Neuropsychiatric testing should be offered to at-risk patients and efforts should be made to ensure each child has an individualized education plan in place as appropriate.

Maturational Progress

Pubertal development and growth are significantly delayed in patients with sickle cell disease. On average, puberty is delayed 1-2 years, and the median age at menarche for girls is 13.2 years. Skeletal age is delayed by 1.3 years in children between the ages of 10-15 years. [Zemel: 2007]

Social & Family Functioning

Family structure should be determined and primary caregivers identified so that they may be educated about acute complications and instructed on the correct technique for splenic palpation. Assessment of family resources should include availability of transportation for appointments and acute visits, a working phone to schedule appointments, and the ability to obtain prescribed medications.

Physical Exam

Patients experiencing acute vaso-occlusive pain crises typically appear distressed and very uncomfortable; although some patients, especially those with frequent pain episodes or chronic pain, may be more stoic or not show the “expected” behaviors of someone with severe pain. The vital signs may be normal. Swelling does not have to be present.

Vital Signs

Abnormalities in vital signs should prompt further evaluation. Hypertension is associated with increased risk of stroke and should be managed aggressively. Pulse oximetry is an inaccurate measurement and often underestimates oxygen saturation in patients with sickle cell disease due to increased levels of carboxyhemoglobin and methemoglobin. Tachypnea or hypoxia should prompt evaluation for acute chest syndrome. Tachycardia and hypertension are not universally present in patients experiencing acute vaso-occlusive pain crises.

Growth Parameters

Children have a decreased growth velocity in proportion to the severity of their anemia.

Skin

Chronic skin ulcers in the lower extremities can develop as a result of small vessel vaso-occlusion, vasoconstriction, decreased oxygenation of skin tissue, or infections.

HEENT/Oral

Adenotonsillar hypertrophy may be a sign of obstructive sleep apnea. In patients with sickle cell disease, obstructive sleep apnea is associated with increased frequency of vaso-occlusive pain crises due to more frequent deoxygenation, which triggers red cell sickling. Children and adolescents with sickle cell disease have an increased risk of retinopathy and may have neovascularization or hemorrhage on retinal exam. Many children will require orthodontia due to maxillary protrusion secondary to compensatory bone marrow expansion (see all Orthodontics services providers (49) in our database).

Chest

Tachypnea, retractions, decreased breath sounds, crackles, or wheezing should prompt evaluation for acute chest syndrome or reactive airway disease.

Heart

Systolic flow murmurs may be present secondary to chronic anemia. An accentuated pulmonic component of the second heart sound or gallop can indicate development of pulmonary hypertension.

Abdomen

Acute splenomegaly may indicate splenic sequestration crisis. Chronic splenomegaly may result in hypersplenism or put patients at risk for splenic rupture. Due to chronic hemolysis, there is an increased risk for cholelithiasis, which can manifest with a positive Murphy’s sign (hypersensitivity to deep palpation in the subcostal area when a patient with gallbladder disease takes a deep breath) or severe right upper quadrant tenderness.

Genitalia

Males with sickle cell disease can develop priapism, a painful and prolonged erection. Delayed pubertal maturity is not uncommon.

Extremities/Musculoskeletal

Limited range of motion with forced internal rotation of the left extremity or painful straight leg raise may be a sign of avascular necrosis of the femoral head. Avascular necrosis in the humeral head may cause similar symptoms in the shoulder. Point tenderness or swelling with fever can occur in the setting of osteomyelitis or bone infarction.

Neurologic Exam

Any new focal neurologic deficit or weakness is a medical emergency and could be a sign of either an acute ischemic or hemorrhagic stroke.

Testing

Sensory Testing

All patients should receive dilated retinal examinations by an ophthalmologist to screen for sickle retinopathy starting at age 10 years. Any child receiving iron chelators should have ophthalmologic examinations yearly.

Patients receiving iron chelation should have audiology screening yearly.

Laboratory Testing

Patients with sickle cell disease should have routine screening of kidney and liver function annually with bloodwork and urinalysis. Patients receiving hydroxyurea therapy on stable doses need complete blood counts performed every 3 months to monitor absolute neutrophil and platelet counts. A complete blood count including reticulocyte count should be obtained when children present with acute sickle-related complaints.

Imaging

Children with Hb SS or sickle β0 thalassemia should receive annual screening with TCD starting at age 2 and continuing through age 16. The relative risk of stroke is 44 in children with abnormal velocities on TCD. [Adams: 1992] Screening with TCD or neuroimaging is not recommended in asymptomatic adults.

Routine screening with echocardiograms is no longer recommended. Patients with new cardiopulmonary symptoms should receive an echocardiogram and be evaluated for asthma or other non-sickle-cell-disease conditions.

Patients receiving chronic transfusions should be screened annually with MRI for hepatic or cardiac siderosis to determine need for oral chelation therapy.

Genetic Testing

Genetic testing is available for mutations in the beta globin gene. Mutation testing may be sent to help distinguish between Hb SS and sickle β0 thalassemia. It can also be used in unusual cases with ambiguous electrophoretic patterns.

Specialty Collaborations & Other Services

Pediatric Ophthalmology (see Services below for local providers)

Refer for annual or bi-annual sickle retinopathy screening beginning at age 10.

Pediatric Pulmonology (see Services below for local providers)

Refer if there is a history of acute chest syndrome, reactive airway disease, or concern for obstructive sleep apnea.

Pediatric Cardiology (see Services below for local providers)

Refer for consideration of cardiac catheterization and management of pulmonary hypertension if TRV >3 m/s on echocardiogram.

Pediatric Neurology (see Services below for local providers)

Refer if there is a history of stroke, cerebral vasculopathy, or silent infarct.

Pediatric Genetic Counseling (see Services below for local providers)

Parents of childbearing age should receive genetic counseling regarding the risk of having another child with sickle cell disease.

Treatment & Management

Overview

The management of sickle cell disease focuses on primary and secondary prevention of complications as well as management of chronic comorbid conditions. The care of all patients with sickle cell disease should be directed/overseen by a clinic that specializes in that care and collaborates with primary care to assure high-quality comprehensive care. Distance from such a center may determine where key care components are delivered. The Sickle Cell Disease National Resource Directory (CDC) lists national agencies, specialty care centers, and community-based organizations that provide services and resources for people affected by sickle cell disease.

Pearls & Alerts for Treatment & Management

L-glutamine for sickle cell disease treatment

The FDA approved the use of L-glutamine powder (Endari) in July 2017 for patients age 5 years and older. It is an oral medication shown to decrease rates of acute chest syndrome, as well as frequency of hospitalization and length of stay for vaso-occlusive pain crises in patients who had 2 or more episodes of pain in the preceding year. It is the first drug to gain FDA-approval for sickle cell disease treatment in more than 2 decades.

Perioperative surgical management

Undergoing general anesthesia for surgical procedures increases the risk for development of acute chest syndrome of vaso-occlusive pain crisis. Preoperative simple or exchange transfusion has been demonstrated to minimize this risk.

How should common problems be managed differently in children with Sickle Cell Disease?

Viral Infections

Patients with sickle cell disease who test positive for influenza should be treated with a therapeutic course of oseltamivir.

Bacterial Infections

Fever of 101ºF (≥38.3ºC) in a patient with sickle cell disease is a medical emergency. The clinician should urgently evaluate the patient, obtain blood cultures, and administer broad spectrum antibiotics (e.g., third-generation cephalosporin). Inpatient admission may be indicated if the patient is <1 years of age, incompletely vaccinated, noncompliant with penicillin prophylaxis, toxic-appearing, or has an elevated white blood count >30k or <5k. In the event of a positive blood culture, patients without adequate outpatient follow-up (e.g., no transportation or working phone) should be observed inpatient.

Systems

Hematology/Oncology

Primary prevention
Children with Hb SS disease or sickle β0 thalassemia should be started on penicillin prophylaxis at diagnosis to prevent pneumococcal sepsis. Prophylaxis may be discontinued at age 5 if there is no history of pneumococcal bacteremia or surgical splenectomy. [Falletta: 1995] All patients should complete a normal immunization series as well as additional meningococcal and pneumococcal vaccines as recommended by the most current version of the Centers for Disease Control and Prevention's Immunization Schedules (CDC).

The 2014 National Heart, Lung, and Blood Institute recommend that hydroxyurea therapy be offered to all patients with homozygous sickle cell anemia or sickle β0 thalassemia starting at 9 months of age regardless of prior complications or baseline fetal hemoglobin percentage. [Yawn: 2014] Hydroxyurea therapy has been shown to decrease frequency of vaso-occlusive pain crises, acute chest syndrome, and lifetime transfusion requirements, as well as increase life expectancy. [Steinberg: 2010] Hydroxyurea for Sickle Cell (Hospital for Sick Children) ( PDF Document

395 KB) is an information sheet for parents with children prescribed hydroxyurea (Hydrea).

Hydroxyurea can cause depression of the absolute neutrophil count. Patients treated with hydroxyurea should be monitored every 3 months with CBCs. The dose is titrated to achieve an absolute neutrophil count between 1,250 and 4,000, with a maximum dose of 35 mg/kg/day. Recommendations for initiation and monitoring of hydroxyurea therapy are summarized in [Yawn: 2014].

Patients with abnormal cerebral velocities measured by transcutaneous Doppler should be treated with chronic red cell transfusions, which has been shown to decrease stroke risk by 90%. [Adams: 1998] New data suggest that children with abnormal TCDs who have had more than 1 year of chronic transfusions may be safely switched to a maximal tolerated dose of hydroxyurea for primary stroke prophylaxis. [Ware: 2016]

Secondary prevention
Patients with prior stroke should begin a chronic transfusion regimen to prevent stroke recurrence. The goal of chronic transfusions is to maintain sickle hemoglobin percentage <30% and maximum hemoglobin <11-12 g/dL. Chronic transfusions are sometimes prescribed for patients with frequent and severe episodes of vaso-occlusive pain or acute chest syndrome.

Iron chelators are prescribed for patients receiving chronic transfusions who have evidence of iron overload. This therapy should be monitored by a hematologist familiar with this medication. Patients will need annual ophthalmology and audiology screening while taking iron chelators.

L-glutamine was approved by the FDA in July 2017 for patients age 5 years and older. This is the first drug to gain approval for sickle cell disease in more than 2 decades. It is an oral medication taken twice daily and has been shown to decrease rates of acute chest syndrome, as well as frequency of hospitalization and length of stay for vaso-occlusive pain crises in patients who had 2 or more episodes of pain in the preceding year. It is well-tolerated with a minimal side effect profile that may include constipation, nausea, abdominal pain, or headache.

Management of acute complications
Vaso-occlusive pain crisis: Patients presenting with painful crises should receive therapy with NSAIDs and opiates. Moderate to severe episodes may require treatment with parenteral opiates and hospitalization. Intravenous fluid hydration can help decrease red blood cell sickling. The Pain Rating Scale (Wong-Baker FACES Foundation) is a self-assessment that uses expressions on faces to depict pain level. The scale can be used with people ages 3 and older to facilitate communication and improve assessment so pain management can be addressed. Sickle Cell: What to Do When Your Child is Experiencing Pain (Children's Hospital Colorado) ( PDF Document

304 KB) lists steps for comforting a child with sickle cell who is experiencing pain and includes medication dosing charts.

Acute chest syndrome: Patients with respiratory symptoms and a new infiltrate on chest radiography should be treated empirically with a third-generation cephalosporin and macrolide antibiotic. Simple or red cell exchange transfusion may be required for worsening respiratory distress.

Splenic sequestration: Patients should be admitted to the hospital for serial examinations and CBCs. Red cell transfusion may be required.

Sickle Cell: When to Call The Doctor (Children's Hospital Colorado) ( PDF Document

287 KB) lists possible symptoms in children with sickle cell disease that may indicate a serious problem and need immediate medical attention.

Specialty Collaborations & Other Services

Pediatric Hematology/Oncology (see Services below for local providers)

Children should be followed by a pediatric hematologist who has expertise in sickle cell disease and hemoglobinopathies and who can provide comprehensive care as well as management of acute complications.

Sickle Cell Disease Centers (see Services below for local providers)

The care of all patients with sickle cell disease should be directed/overseen by a clinic that specializes in that care and collaborates with primary care to assure high-quality comprehensive care. Distance from such a center may determine where key care components are delivered.

Audiology (see Services below for local providers)

Children and adolescents will need annual screening while taking iron chelators.

Pediatric Ophthalmology (see Services below for local providers)

Children and adolescents will need annual screening while taking iron chelators.

Neurology

Neuropsychologic testing should be offered to patients with history of stroke, abnormal TCDs or school underperformance and efforts should be made to ensure each child has an individualized education plan in place as appropriate. The treatment of ischemic stroke in patients with sickle cell disease is immediate red cell exchange transfusion with a goal of decreasing sickle percentage to <30% with an end hemoglobin of 10 g/dL. This differs significantly from thrombolytic therapy used in the general population. Referral to a sickle cell expert is recommended for those with silent infarct, which are usually picked up on imaging performed to rule out acute stroke (found in an anatomic area that does not explain the acute symptoms) or cerebral vasculopathy (moyamoya).

Specialty Collaborations & Other Services

Pediatric Neurology (see Services below for local providers)

Patients with a history of overt stroke or cerebral vasculopathy should be referred for annual follow-up. Neurology will continue to monitor for progression of cerebral vasculopathy, which might warrant intervention with the encephaloduroarteriosynangiosis (EDAS) procedure.

Neuropsychiatry/Neuropsychology (see Services below for local providers)

Patients with impaired school performance or history of silent cerebral infarction or overt stroke should be referred for formal neuropsychology assessment. Appropriate learning accommodations should be made within the context of an IEP or 504 plan based on these results.

Renal

Sickling of red blood cells in the renal glomeruli causes urinary concentrating defects or hyposthenuria. This can manifest as nocturnal enuresis or nocturia in otherwise continent children. This complication may need pharmacologic intervention such as DDAVP in addition to the typical behavioral modifications approaches to enuresis recommended by primary care providers.

Specialty Collaborations & Other Services

Pediatric Nephrology (see Services below for local providers)

Refer patients with significant proteinuria or abnormal kidney function for evaluation and collaborative management.

Recreation & Leisure

Considerations when making activity level recommendations may include:

Child with Sickle Cell Climbing - Recreational Considerations for Children with Sickle Cell

Camp ASCCA

Avoid handling reptiles and amphibians (turtles, lizards, frogs, etc.) due to increased risk of Salmonella infection. See Animals that May Carry Salmonella (CDC) for a more extensive list.
Participate in sports and other physical activities, but remain hydrated at all times.
Avoid environmental exposure to severe cold, which may precipitate vasoconstriction and painful crises.
If residing at sea level, do not travel to an altitude above 7,500 feet due to the risk for painful crises and splenic infarction secondary to hypoxia.

Depending on the temperature and humidity, swimming in outdoor unheated pools can precipitate pain crises due to evaporative cooling.

Learning/Education/Schools

By the age of 5 years, 20% of patients with Hb SS disease have evidence of prior silent cerebral infarction. This increases to 37% by 14 years of age. Patients with silent cerebral infarcts have impaired academic achievement and commonly have decreases in attention and executive functioning that can impact organizational and problem-solving skills. Individuals also have decreased IQ compared to other patients with sickle cell disease who have not had a silent cerebral infarction. Students should have an individualized education plan targeting their specific deficits identified on neuropsychology testing. Interventions may be aimed at treating inattention or impulsivity and providing accommodations, such as additional time to complete tests. [Schatz: 2001]

Transitions

Historically, sickle cell disease had been a pediatric disorder; however, with the advent of modern comprehensive sickle cell care, the majority of patients now survive into adulthood and require transition of care to an adult providers. This transition is a vulnerable time for these adolescents. Studies have shown worse health outcomes and increased health care utilization in the young adult population as they transition out of pediatric care. Transitioning individuals have increased rates of emergency department visits and decreased access to chronic therapy, such as hydroxyurea. [Hemker: 2011] [Blinder: 2015]

Elements essential for successful transition from pediatric to adult sickle cell care include counseling the patient about the transition prior to transfer; communicating among pediatric and adult providers, ensuring that the first visit to an adult provider is before the final pediatric visit or within 1-3 months of the last pediatric visit. [Sobota: 2017] Potential quality indicators for successful transition are:

The individual is keeping clinic appointments and remaining adherent to treatment and medications.
The written transfer summary has been sent to the adult provider.
The first visit to adult provider is within an appropriate interval after leaving pediatric hematology.
Overall quality of life is good.

Issues Related to Sickle Cell Disease

Education & Schools

Funding & Access to Care

Writing Letters of Medical Necessity

Ask the Specialist

How do I interpret the newborn screening report and what should I do if the results are consistent with possible sickle cell disease?

The newborn screening report will list the types of hemoglobin present in decreasing order of relative quantity. Because fetal hemoglobin is most common in the first several weeks of life, it is always listed first in untransfused babies. Normal infants should have a screen showing “F+A”. Patients with one of the sickling disorders may have newborn screens showing “F+S”, “F+S+A” or “F+S+C”. Patients with “F+A+S” have sickle cell trait.

If a child’s newborn screen results are consistent with possible sickle cell disease, the state newborn screening lab will provide instructions for sending a second newborn screen to confirm the abnormal hemoglobin pattern. If sickle cell disease is confirmed, the patient should be referred to pediatric hematology or a comprehensive sickle cell center. Penicillin prophylaxis should be prescribed by two months of age for patients with severe phenotypes (homozygous sickle cell anemia or sickle beta0 thalassemia) if there is a delay in subspecialty evaluation. Sickle Cell Disease has further Information about initial clinical response to a positive newborn screen.

What additional immunizations to patients with sickle cell disease need?

You should consult the latest version of the CDC Immunization Schedule for high-risk patients with functional or anatomic splenectomy for details as this may change annually.

Patients with sickle cell disease should receive annual influenza immunization. Because of the functional asplenia, they are at increased risk for infection with encapsulated organisms. Therefore, they should complete the normal pneumococcal series with PCV13 as well as a dose of PPSV23 after the age of 2 and at least 8 weeks after the last PCV13. A single booster of PPSV23 should be administered 5 years after the last dose of PPSV23. Primary meningococcal vaccination should occur early with two doses given 8 weeks apart starting at age 2 years. They should also receive meningococcal B vaccination.

What counseling should I perform for a patient with sickle cell trait?

Sickle cell trait is common with a prevalence of up to 1 in 20 in African Americans. It is appropriate for primary care providers to provide counseling to patients regarding their sickle cell trait status. It is important that patients know they do not have sickle cell disease. Patients with sickle trait rarely have health problems. In some extreme conditions, such as severe dehydration or high altitude, there may be complications such as rhabdomyolysis or splenic infarction. Sometimes patients with sickle trait may have blood in their urine and should notify their doctor immediately if this happens.

Patients should also be made aware of the reproductive implications of their trait status. If their partner also has sickle trait or beta thalassemia trait, then their offspring have a 25% chance of having sickle cell disease. We encourage patients to discuss their partner’s trait status prior to conceiving.

Do patients with sickle cell trait experience any symptoms or complications?

In general, individuals with sickle cell trait are asymptomatic and do not experience sickle-related complications like pain. Some data suggest individuals with sickle trait may be at slightly increased risk for renal complications (hematuria), venous thromboembolism (PE) in adulthood, and rarely experience splenic infarction when exposure to altitude. Testing for sickle cell trait is required by the NCAA for college athletes as there have been rare cases of exercise-related complications in individuals who carry sickle cell trait .[Naik: 2015]

Resources for Clinicians

On the Web

Sickle Cell Disease
Information about initial clinical response to a positive newborn screen; Medical Home Portal.

Evidence-Based Management of Sickle Cell Disease (NIH) ( PDF Document 3.2 MB)
Synthesizes the available scientific evidence on sickle cell disease and offers guidance to busy primary care clinicians; Expert Panel Report, 2014, National Institutes of Health.

Sickle Cell Disease (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information; U.S. National Library of Medicine.

Helpful Articles

PubMed search for articles published in the last year about sickle cell disease in children

Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, Guthrie TH, Knight-Madden J, Alvarez OA, Gordeuk VR, Gualandro S, Colella MP, Smith WR, Rollins SA, Stocker JW, Rother RP.
Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease.
N Engl J Med. 2017;376(5):429-439. PubMed abstract / Full Text

Piel FB, Steinberg MH, Rees DC.
Sickle Cell Disease.
N Engl J Med. 2017;376(16):1561-1573. PubMed abstract

Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, Caccavelli L, Neven B, Bourget P, El Nemer W, Bartolucci P, Weber L, Puy H, Meritet JF, Grevent D, Beuzard Y, Chrétien S, Lefebvre T, Ross RW, Negre O, Veres G, Sandler L, Soni S, de Montalembert M, Blanche S, Leboulch P, Cavazzana M.
Gene Therapy in a Patient with Sickle Cell Disease.
N Engl J Med. 2017;376(9):848-855. PubMed abstract

Wang CJ, Kavanagh PL, Little AA, Holliman JB, Sprinz PG.
Quality-of-care indicators for children with sickle cell disease.
Pediatrics. 2011;128(3):484-93. PubMed abstract

Clinical Tools

Assessment Tools/Scales

Pain Rating Scale (Wong-Baker FACES Foundation)
Self-assessment that uses expressions on faces to depict pain level.

Patient Education & Instructions

Sickle Cell: What to Do When Your Child is Experiencing Pain (Children's Hospital Colorado) ( PDF Document 304 KB)
Steps for comforting a child with sickle cell who is experiencing pain; includes medication dosing charts and suggestions for when to call your doctor.

Sickle Cell: When to Call The Doctor (Children's Hospital Colorado) ( PDF Document 287 KB)
Symptoms in children with sickle cell disease that may indicate a serious problem and need immediate medical attention.

Hydroxyurea for Sickle Cell (Hospital for Sick Children) ( PDF Document 395 KB)
Information sheet for parents with children prescribed hydroxyurea (Hydrea). The handout has information about side effects and instructions for how to administer hydroxyurea, what to do if a dose is missed, and safety measures to prevent infections.

Resources for Patients & Families

Books

Platt AF, Eckman J, Hsu L.
Hope & Destiny: The Patient and Parent's Guide to Sickle Cell Disease and Sickle Cell Trait.
4th ed. Hilton Publishing; 2016. 098475668X https://www.amazon.com/Hope-Destiny-Patient-Parents-Disease/dp/0984756...
A 260-page book that offers in-depth information about research, treatment, pain management, and preventing complications.

Information on the Web

For Parents & Families (Medical Home Portal)
Information for parents to help them better care for their child with Rett syndrome (and other complex conditions) from diagnosis through their child's transition to adult care.

Sickle Cell Disease (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

Sickle Cell Disease Fact Sheets and Guides (CDC)
Fact sheets, toolkits, and guides about the many aspects of living with sickle cell disease; Centers for Disease Control and Prevention.

National & Local Support

Sickle Cell Disease Association of America
The mission of this nonprofit is to improve the quality of health, life, and services for individuals, families, and communities affected by sickle cell disease and related conditions while promoting the search for a cure.

Studies/Registries

Sickle Cell Disease (ClinicalTrials.gov)

Services for Patients & Families in Montana (MT)

The Sickle Cell Disease National Resource Directory (CDC) lists national agencies, specialty care centers, and community-based organizations that provide services and resources for people affected by sickle cell disease.

Service Categories	MT	NW		ID	NM	NV	RI
Audiology	48	1	30	300	5	20	51
Neuropsychiatry/Neuropsychology	3		3		8	6	18
Orthodontics	49			6	5		22
Pediatric Cardiology	16	1	4	47	4	16	6
Pediatric Genetic Counseling	5		4	66	1	2	5
Pediatric Hematology/Oncology	10		1	3	3	9	1
Pediatric Nephrology	2		1	5	2	8	1
Pediatric Neurology	14		3	33	7	11	5
Pediatric Ophthalmology	14	1	8	8	5	7	6
Pediatric Pulmonology	6		1	5	5	10	4
Sickle Cell Disease Centers		1					1

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: November 2017; last update/revision: November 2017

Current Authors and Reviewers:

Author:	Christopher McKinney, MD
Contributing Author:	Rachelle Nuss, MD
Senior Author:	Kathryn L. Hassell, MD

Bibliography

Adams R, McKie V, Nichols F, Carl E, Zhang DL, McKie K, Figueroa R, Litaker M, Thompson W, Hess D.
The use of transcranial ultrasonography to predict stroke in sickle cell disease.
N Engl J Med. 1992;326(9):605-10. PubMed abstract

Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A, Nichols FT, Bonds DR, Brambilla D.
Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography.
N Engl J Med. 1998;339(1):5-11. PubMed abstract

Blinder MA, Duh MS, Sasane M, Trahey A, Paley C, Vekeman F.
Age-Related Emergency Department Reliance in Patients with Sickle Cell Disease.
J Emerg Med. 2015;49(4):513-522.e1. PubMed abstract

DeBaun MR, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik SA, Meier ER, Howard TH, Majumdar S, Inusa BP, Telfer PT, Kirby-Allen M, McCavit TL, Kamdem A, Airewele G, Woods GM, Berman B, Panepinto JA, Fuh BR, Kwiatkowski JL, King AA, Fixler JM, Rhodes MM, Thompson AA, Heiny ME, Redding-Lallinger RC, Kirkham FJ, Dixon N, Gonzalez CE, Kalinyak KA, Quinn CT, Strouse JJ, Miller JP, Lehmann H, Kraut MA, Ball WS Jr, Hirtz D, Casella JF.
Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia.
N Engl J Med. 2014;371(8):699-710. PubMed abstract / Full Text

Elmariah H, Garrett ME, De Castro LM, Jonassaint JC, Ataga KI, Eckman JR, Ashley-Koch AE, Telen MJ.
Factors associated with survival in a contemporary adult sickle cell disease cohort.
Am J Hematol. 2014;89(5):530-5. PubMed abstract / Full Text

Falletta JM, Woods GM, Verter JI, Buchanan GR, Pegelow CH, Iyer RV, Miller ST, Holbrook CT, Kinney TR, Vichinsky E.
Discontinuing penicillin prophylaxis in children with sickle cell anemia. Prophylactic Penicillin Study II.
J Pediatr. 1995;127(5):685-90. PubMed abstract

Hassell KL.
Population estimates of sickle cell disease in the U.S.
Am J Prev Med. 2010;38(4 Suppl):S512-21. PubMed abstract

Hemker BG, Brousseau DC, Yan K, Hoffmann RG, Panepinto JA.
When children with sickle-cell disease become adults: lack of outpatient care leads to increased use of the emergency department.
Am J Hematol. 2011;86(10):863-5. PubMed abstract

Lorey FW, Arnopp J, Cunningham GC.
Distribution of hemoglobinopathy variants by ethnicity in a multiethnic state.
Genet Epidemiol. 1996;13(5):501-12. PubMed abstract

Naik RP, Haywood C Jr.
Sickle cell trait diagnosis: clinical and social implications.
Hematology Am Soc Hematol Educ Program. 2015;2015:160-7. PubMed abstract / Full Text

Piel FB, Steinberg MH, Rees DC.
Sickle Cell Disease.
N Engl J Med. 2017;376(16):1561-1573. PubMed abstract

Schatz J, Brown RT, Pascual JM, Hsu L, DeBaun MR.
Poor school and cognitive functioning with silent cerebral infarcts and sickle cell disease.
Neurology. 2001;56(8):1109-11. PubMed abstract

Sobota AE, Shah N, Mack JW.
Development of quality indicators for transition from pediatric to adult care in sickle cell disease: A modified Delphi survey of adult providers.
Pediatr Blood Cancer. 2017;64(6). PubMed abstract

Steinberg MH, McCarthy WF, Castro O, Ballas SK, Armstrong FD, Smith W, Ataga K, Swerdlow P, Kutlar A, DeCastro L, Waclawiw MA.
The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up.
Am J Hematol. 2010;85(6):403-8. PubMed abstract / Full Text

Wang CJ, Kavanagh PL, Little AA, Holliman JB, Sprinz PG.
Quality-of-care indicators for children with sickle cell disease.
Pediatrics. 2011;128(3):484-93. PubMed abstract

Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, Odame I, Fuh B, George A, Owen W, Luchtman-Jones L, Rogers ZR, Hilliard L, Gauger C, Piccone C, Lee MT, Kwiatkowski JL, Jackson S, Miller ST, Roberts C, Heeney MM, Kalfa TA, Nelson S, Imran H, Nottage K, Alvarez O, Rhodes M, Thompson AA, Rothman JA, Helton KJ, Roberts D, Coleman J, Bonner MJ, Kutlar A, Patel N, Wood J, Piller L, Wei P, Luden J, Mortier NA, Stuber SE, Luban NL, Cohen AR, Pressel S, Adams RJ.
Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.
Lancet. 2016;387(10019):661-70. PubMed abstract

Zemel BS, Kawchak DA, Ohene-Frempong K, Schall JI, Stallings VA.
Effects of delayed pubertal development, nutritional status, and disease severity on longitudinal patterns of growth failure in children with sickle cell disease.
Pediatr Res. 2007;61(5 Pt 1):607-13. PubMed abstract