Sickle cell disease (SCD) is a group of complex genetic disorders of hemoglobin with multisystem manifestations. The scope of this clinical report is such that in-depth recommendations for management of all complications is not possible. Rather, the authors present an overview focused on the practical management of children and adolescents with SCD and the complications that are of particular relevance to pediatric primary care providers. References with detailed commentary provide further information. Timely and appropriate treatment of acute illness is critical, because life-threatening complications may develop rapidly. Specialized comprehensive medical care decreases morbidity and mortality during childhood. The provision of comprehensive care is a time-intensive endeavor that includes ongoing patient and family education, periodic comprehensive evaluations and other disease-specific health maintenance services, nursing support, psychosocial care, and genetic counseling. Ideally, this care includes comanagement by the pediatrician or other pediatric primary care provider and a team of specialist SCD experts: Hematologist, other pediatric specialists, advanced practice providers, nurse specialists, social workers, patient navigators, and educational liaisons.
Introduction
Sickle cell disease (SCD) describes a group of complex chronic disorders characterized by hemolysis, unpredictable acute complications that may rapidly become life-threatening, and the variable development of chronic organ damage. Expert comprehensive medical care decreases morbidity and prolongs life expectancy for individuals with SCD.1–6 Many children and adolescents with SCD in the United States receive much, if not all, of their medical care from pediatricians and other pediatric primary care providers. This report is intended to provide the pediatric primary care provider with an overview of the essential components of comprehensive care for children and adolescents with SCD and their families regardless of where it occurs, and thus facilitate the comfort of both providers and patients. It represents a literature-based consensus of expert opinion, not a systematic review, with the goal of providing practical guidance, both anticipatory and responses to complications, for care of children and adolescents with SCD. Recent publications detail specific ideal components of comprehensive SCD centers.6–9
The sickle gene arose in West Africa 50 000 years ago and persisted because of the protection it may convey against cerebral malaria. It spread by migration and the trade of enslaved persons to North Africa, Italy, Turkey, Greece, India, the Caribbean, and the Americas, and occurs today in descendants from all of these areas. In the western world, SCD has largely been viewed as a disorder of people of color (although it occurs in all racial and ethnic groups), and medical services for this population have been limited by access to care related to socioeconomic inequity, historic underinvestment in research for therapeutic development, and systemic racism.10,11 Racism, in all its forms, including structural, institutional, personally mediated, and internalized, whether implicit or explicit, negatively impacts medical care, particularly for persons with SCD.12 Solving these problems will require long-term societal changes, but medical providers can begin by addressing their own approach to persons with SCD. One first step is to stop using the depersonalizing term “sickler” for people with SCD and educating colleagues who do. An additional step is to practice personal mindfulness by recognizing that everyone has biases and acknowledging that the challenges faced by patients may not be evident to a practitioner.13 This process may be aided by universal screening for social drivers of health to help ensure that patients and families have their concerns heard. In addition, helping all staff members, both clinical and administrative, to become aware of and sensitive to the needs and realities of persons with SCD will help to foster the trust of patients and families that racism has no place in medical care.10–12,14
Although more than 98% of children born with SCD will survive to transition to adult care, median life expectancy for someone born with sickle cell anemia (HbSS) in the United States is the fifth decade, 2 decades less than individuals of similar race without SCD, a finding that has not improved substantially in the last 25 years.2,15–17 Improving equity of care for, and increasing knowledge of how to care for, persons with SCD by all health care providers is the goal of this report.
Overview of Pathophysiology
SCD is an autosomal recessive genetic disorder characterized by the presence of sickle hemoglobin (HbS) in red blood cells. Four genotypes, HbSS, sickle hemoglobin C disease (HbSC), and 2 types of sickle β-thalassemia (Sβ+-thalassemia and Sβ0-thalassemia; determined by the amount of hemoglobin A produced), are the most common. Rare forms of SCD are caused by coinheritance of HbS with other hemoglobin variants, such as hemoglobin D-Punjab, hemoglobin E, or hemoglobin O-Arab. A single amino acid change in the beta globin gene causes polymerization of deoxygenated hemoglobin, leading to sickle or crescent-shaped red blood cells. The sickled red blood cells result in hemolysis and intermittent episodes of vascular occlusion that cause tissue ischemia leading to acute and chronic organ dysfunction. Potential acute and chronic manifestations of SCD during childhood and adolescence are shown in Fig 1. Generally, children with HbSS and Sβ0-thalassemia are more severely affected than are children with HbSC or Sβ+-thalassemia. However, each genotype is characterized by marked and largely unpredictable variability in clinical expression and severity.18
Complications of SCD. Additional complications: Anemia, delayed growth, and sexual maturation. * Potential cause of mortality.
Complications of SCD. Additional complications: Anemia, delayed growth, and sexual maturation. * Potential cause of mortality.
Diagnosis and Establishment of Care
Infants with SCD are healthy at birth and develop symptoms early in infancy or childhood as the fetal hemoglobin level declines. All 50 states, the District of Columbia, Puerto Rico, the US Virgin Islands, and the US military have some form of newborn screening (NBS) for hemoglobinopathy capable of making a definitive diagnosis of SCD at birth.19 Pediatricians and pediatric primary care providers are advised to be familiar with their state screening programs, record the result of the hemoglobinopathy screening test (disease, trait, or normal) in the medical record, educate the family when those results are shared with them, and rediscuss the finding in adolescence and at transition to adult care.20,21 Depending on local care resources, sometimes the pediatric primary care provider is the only source of care for children with SCD. This document seeks to offer best practice information and provide support to fulfill this role.
Ideally, an NBS finding of SCD results in consultation, and most often referral, to a pediatric SCD center or pediatric hematologist for comprehensive care comanagement, with the first visit occurring before 3 months of age. An NBS finding of trait or disease requires education of the parents regarding the potential future risk of their conceiving a subsequent child with SCD.22,23 In addition, it is important that the results of testing on previously born siblings, including the presence of sickle cell trait, are reviewed and discussed with the family at diagnosis and with that child at least at school entry, preadolescence, and transition visits (Table 1). If NBS results are not available, particularly for children born outside the United States, adolescents, or patients who transfer into a practice beyond infancy, a hemoglobinopathy evaluation (hemoglobin electrophoresis, high-performance liquid chromatography, isoelectric focusing, or similar testing) is appropriate as soon as possible.20 If transfusion has occurred, hemoglobinopathy testing is postponed for 3 months, or genetic testing may be performed. Programs like The Innovations in Newborn Screening Interoperability Resource Center and Learning Collaborative, funded by the Health Resources and Services Administration, which seeks to improve data exchange and interoperability between state newborn screening and electronic health record systems, may make locating and sharing this information easier in the future.24
Neonatal Screening and Diagnostic Test Results
Disorder . | Newborn Screening Results . | Hemoglobin Separation Mid-Childhood . | Hemoglobin (g/dL) Mid-Childhood . | MCV (fL) . |
---|---|---|---|---|
HbSS | FS | S | Decreased | Normal to increased |
HbSC | FSC | SC | Decreased | Normal |
SB+-thalassemia | FSA | SA | Decreased to normal | Decreased |
SB0-thalassemia | FS | S | Decreased | Decreased |
S trait | FAS | AS | Normal | Normal |
Disorder . | Newborn Screening Results . | Hemoglobin Separation Mid-Childhood . | Hemoglobin (g/dL) Mid-Childhood . | MCV (fL) . |
---|---|---|---|---|
HbSS | FS | S | Decreased | Normal to increased |
HbSC | FSC | SC | Decreased | Normal |
SB+-thalassemia | FSA | SA | Decreased to normal | Decreased |
SB0-thalassemia | FS | S | Decreased | Decreased |
S trait | FAS | AS | Normal | Normal |
Table shows typical results; exceptions occur. Hemoglobins are reported in order of quantity (eg, FSA = F>S>A).
Complications of Sickle Cell Disease
Acute Illness
Acute illness characterized by common childhood signs and symptoms such as fever, cough, abdominal pain, pallor, or a limp, can rapidly become life-threatening in SCD.1,6 Identification of a medical facility with around-the-clock access to knowledgeable care for evaluation and treatment of SCD is a key component of anticipatory care management for every child with SCD.
Health care professionals who treat acute illness need access to baseline information about the patient (eg, SCD genotype, the presence or absence of splenomegaly, prior splenectomy, chronic complications, usual pulse oximetry values, baseline complete blood cell count [CBC], and reticulocyte counts). Strategies for ensuring the availability of baseline information about individual patients include computerized patient databases and/or the provision of this information directly to patients and families on medical alert cards or on emergency information forms as recommended by the American Academy of Pediatrics.25 The goal of ensuring timely medical treatment of acute illness also is facilitated by providing anticipatory guidance to patients and families about early recognition, appropriate medical evaluation, and treatment of common acute complications.6 Examples of acute and chronic complications are outlined briefly below and in Fig 1.26 More than 1 complication may be present simultaneously.
Red Blood Cell Transfusion
For many acute and chronic complications of SCD, red blood cell transfusion may be required. To minimize the risk of alloimmunization to minor red cell antigens, an extended red blood cell antigen profile, by genotype or serology, is determined prior to the first transfusion and optimally in infancy. Thus, extended, antigen-matched red blood cells (at least for C, E, and Kell antigens) can be transfused when needed.6,27,28
Fever
Because patients with SCD may develop splenic dysfunction as early as 3 months of age, they are at high risk for septicemia and meningitis with Streptococcus pneumoniae and other encapsulated bacteria.29 Thus, all children with SCD and a temperature ≥38 to 38.5°C (≥100.4–101.3°F) require rapid triage and examination, urgent CBC and reticulocyte counts, blood culture, and prompt administration of a broad spectrum parenteral antibiotic, such as ceftriaxone sodium.6,30 Because of its long half-life, ceftriaxone is preferred when outpatient management with close follow-up is planned. Other testing, such as for infection with influenza or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), chest radiographs, and cerebrospinal fluid or urine cultures are obtained only for standard clinical indications. The presence of a focus of infection (eg, viral upper respiratory illness, otitis media, coronavirus disease 2019/SARS-CoV-2) or prior receipt of immunizations does not alter the urgency of and need for administering parenteral antibiotics. Vancomycin hydrochloride may be added for suspected meningitis and/or sepsis, based on local susceptibility patterns. Infections such as osteomyelitis, often caused by Staphylococcus aureus and Salmonella species, are initially treated with a broad-spectrum antibiotic and vancomycin pending the results of culture and sensitivities. Other acute complications of SCD, such as acute chest syndrome, splenic sequestration, and transient aplastic crisis, also need to be evaluated for during febrile illness.
Pain
Unpredictable episodes of severe and sometimes excruciating pain are the hallmark of SCD.31,32 Many uncomplicated episodes of pain can be managed at home with oral fluids, rest, heat, oral analgesics (using full doses of both mild opioid and nonsteroidal antiinflammatory medications, as per their pharmacology), comfort measures, and distraction. Nonpharmacologic methods of pain control, taught to the patient and family previously, are reinforced during the acute pain event.33 When home management measures fail to adequately manage pain, it is essential that patients receive rapid triage, assessment, and aggressive, appropriately monitored parenteral analgesia in medical facilities. For severe pain, parenteral opioids, such as morphine, are indicated and administered by scheduled around-the-clock dosing or patient-controlled analgesia.6,32–34 Other issues include adequate maintenance of (but avoidance of excessive) hydration, monitoring of oxygenation and cardiorespiratory status, use of incentive spirometry to encourage deep inspiratory effort,35 and close observation for the development of other complications, particularly acute chest syndrome.36 During episodes of severe pain, additional life-threatening complications may develop rapidly and often are heralded by a suddenly increasing oxygen requirement, altered mental status, or declining hemoglobin level or platelet count.37 It is important to note that transfusion is of no acute benefit for resolution of painful episodes.
Patients are particularly at risk for discrimination in analgesic management of the severe, recurrent, and sometimes chronic pain that occurs in SCD. Because there are rarely any objective physical findings with or identifiable “cause” of even severe pain, persons with SCD may be stigmatized when seeking pain relief.11,12 Delays in addressing, and undertreatment of, SCD pain are common. Further, studies have documented disparities in pain management between racial groups, with children of color receiving less pain medication for appendicitis or fractures, as well as later recognition of sepsis and fewer antibiotics for equivalent infections.38–41 If pain is present, it is to be treated aggressively, and, if possible, according to a predetermined personalized analgesic plan of care. In SCD, the children and their caregivers know their disease best, and as far as possible, all actions should be the result of shared decision-making by patient, family, and the health care team. Pediatric providers should work to foster the trust of their patients that they will be heard, particularly when in pain. These efforts will help to ensure the provision of optimal care, and work to mitigate the effects of systemic racism, which causes families to mistrust the health care system, leading to children with SCD being less likely to adhere to best care practices.10,42–44
Acute Chest Syndrome
Acute chest syndrome is a life-threatening complication characterized by a new segmental infiltrate identified on a chest radiograph (which may not be visible on first presentation), accompanied by lower respiratory tract symptoms, chest pain, and/or hypoxemia.36,45 Acute chest syndrome can present acutely or after initial presentation for a pain event and with or without fever. Children with SCD and reactive airway disease have an increased incidence of acute chest syndrome.46 Acute chest syndrome is also a potential complication following general anesthesia related to hypoventilation (often related to inadequately treated thoraco-abdominal pain) and reduced inspiratory effort. Other specific causative factors of acute chest syndrome may include infection (viral, bacterial, Mycoplasma, or Chlamydia), pulmonary infarction, and pulmonary fat embolism. Patients may deteriorate rapidly with progression to pulmonary failure and death. Early recognition and aggressive treatment with oxygen, incentive spirometry, analgesics, antibiotics, and often, simple or exchange transfusions, may be lifesaving.36,45 Red blood cell transfusion, oxygen, or ventilatory support in a PICU may be required.
Splenic Sequestration
Splenic sequestration is an acute illness characterized by a rapidly enlarging spleen and a decrease in hemoglobin level of more than 2 g/dL below the patient’s baseline value.6 Mild to moderate thrombocytopenia is often present. Severe cases may rapidly progress to shock and death. Prompt recognition and careful administration of red blood cell transfusions, when appropriate, may be lifesaving.47–49 Care must be taken to avoid acute overtransfusion to a hemoglobin greater than 10 g/dL, as sequestered red cells may be acutely released from the spleen as the acute event resolves. Practically, transfusions of 3 to 5 mg/kg are used, and a posttransfusion hemoglobin is checked before the next aliquot of red cells is ordered. Although splenic sequestration is most common in children with HbSS younger than 5 years and adolescents with HbSC, it may occur at any age in patients with any form of SCD. Parents and caregivers of young children with SCD are taught to check their child’s spleen daily so they recognize enlargement early and urgently seek medical attention.50 Surgical splenectomy to prevent recurrence may be recommended after recovery from life-threatening or recurrent episodes.6
Transient Aplastic Crisis
Transient aplastic crisis is characterized by an exacerbation of the patient’s baseline anemia with a substantially decreased reticulocyte count, typically to below 1%.6 Recognition requires comparison of CBC and reticulocyte counts obtained during acute illness with baseline values. Red blood cell transfusions are often needed. Acute infection with human parvovirus B19, usually without the characteristic rash, is the most common cause.51 Parvovirus is highly contagious, so isolation of suspected cases from at-risk persons, such as pregnant health care professionals or others with chronic hemolysis, is recommended.52 Siblings and others with SCD in contact with the patient are also at risk for concurrent or subsequent aplastic crisis, and a hemoglobin and reticulocyte count is checked.
Stroke
Any acute neurologic symptom other than transient mild headache requires urgent evaluation.53,54 Common presenting symptoms and signs of stroke include hemiparesis, aphasia or dysphasia, seizures, monoparesis, severe headache, cranial nerve palsy, stupor, and coma. Initial evaluation includes a CBC, reticulocyte count, blood type and crossmatch, and noncontrast computed tomography or MRI of the brain to exclude hemorrhage.6,54,55 Acute treatment may include partial exchange transfusion or erythrocytapheresis (red cell exchange transfusion) to reduce HbS to <30% and raise hemoglobin to 10 g/dL. MRI, including diffusion-weighted imaging and magnetic resonance angiography (MRA), are used to characterize the stroke and determine whether large vessel vasculopathy is present. After a stroke, a lifelong chronic transfusion program for secondary stroke prevention is recommended.6,56,57
To identify children with HbSS or sickle β0-thalassemia at highest risk of stroke, transcranial Doppler ultrasonography screening is performed yearly between 2 and 16 years of age.6,53,54 Elevated velocity may indicate a need to initiate a chronic blood transfusion program for primary stroke prevention.57,58 After at least 1 year of chronic transfusion, a select group of children whose velocities have normalized may transition to hydroxyurea therapy.59,60 Silent ischemic injury can also occur in SCD and children may present with subtle findings such as developmental delay or poor school performance. MRI/MRA is required to detect such events.54,61 (See also section on Comprehensive Medical Evaluation below.)
Kidney
Loss of renal concentrating ability (hyposthenuria) affects many persons with SCD starting in infancy and may lead to prolonged issues with enuresis. Fluid restriction may lead to dehydration and, thus, promote intravascular sickling with an increase in painful events. Management includes supportive counseling about the cause of enuresis (related to urinary concentrating deficit of SCD and not behavioral), timed overnight waking to void, and waterproof mattress covers.62 Renal papillary necrosis presents with painless macroscopic (gross) hematuria attributable to infarction of the renal papillae. Evaluation includes urinalysis, urine culture, abdominal ultrasonography, and screening coagulation tests. Treatment is usually bed rest and hydration. Proteinuria may develop in later childhood or adolescence and may progress to renal insufficiency. Annual screening for elevated urinary protein, by protein (albumin)-to-creatinine ratio, begins by age 10.6 If repeatedly elevated, screening of first morning voided urine sample for elevated protein-to-creatine ratio and referral to nephrology is advised.63
Priapism
Priapism is a prolonged painful erection that commonly occurs in children and adolescents with SCD, often starting during the early morning hours.64,65 It occurs in 2 forms:
1. stuttering episodes that typically last <4 hours but are often recurrent; and
2. severe acute ischemic episodes that last ≥4 hours and may eventually result in impotence.
Priapism is treated as a painful event with hydration and analgesia, often at home, unless it lasts more than 4 hours, when irreversible tissue damage may start to occur. Severe acute episodes with a continued erection ≥4 hours require emergent medical evaluation, including urgent urologic consultation, and may require penile aspiration and irrigation in addition to intravenous hydration and analgesia, including opioids, for relief.66,67
Chronic Manifestations
Many potential chronic manifestations of SCD are also shown in Fig 1.26,68 It is important to note that the anemia that may occur in conjunction with SCD will not improve with iron supplementation. Medicinal iron is not given unless iron deficiency is biochemically proven because of the potential risk of lifetime iron overload from repeated red blood cell transfusions. Pica is common, but is not related to iron status in SCD. Splenomegaly may become chronic and require splenectomy. Cardiomegaly may occur. Evaluation for gallstones may be indicated for a child with SCD and right upper quadrant pain, frequent episodes of vomiting, and/or worsening jaundice. Children with SCD have a higher incidence of obstructive lung disease, which may become restrictive as they get older. Pulmonary hypertension more frequently occurs in adults but may present during childhood. Avascular necrosis of hips or shoulders is common. Proliferative retinopathy, which may lead to retinal detachment, is possible in all types of SCD but especially persons with HbSC.69 Poorly healing ulcers, especially around the ankles, may require the assistance of a wound care expert. Even in the absence of overt or silent stroke, children with SCD may have neuropsychologic impairment that impacts school and job performance.54,70
Review of Care
Overview of Comprehensive Care and Comanagement
SCD is a complex disorder with multisystem manifestations requiring comprehensive care from both a pediatrician or other pediatric primary care provider and a multidisciplinary SCD clinic team.14 Ideally, the pediatric primary care provider manages all aspects of general pediatric care71 and comanages SCD-specific manifestations (complications) with the SCD team.7–9 The patient and family are involved in all decisions, including where care occurs. Similar to other chronic illnesses, age, socioeconomic status, and medical/neurobehavioral comorbidities negatively affect health-related quality of life. Thus, for persons with SCD, racial bias complicates all care.43,72,73
SCD-specific care, as outlined by a National Institutes of Health consensus statement and expert opinion, may require equipment and resources not available in many pediatric primary care settings.6,73 The extent to which the comprehensive care outlined in this report is delivered by pediatric primary care practices versus a multidisciplinary specialist sickle cell clinic will vary by community and will depend on the comfort of the primary care provider, availability of local resources, preferences of the family, as well as the frequency and severity of SCD manifestations. However, at least an annual consultation with a multidisciplinary SCD team is strongly advised. Remote virtual visit programs involving the pediatric primary care provider and SCD specialist may be available. Some SCD programs support primary pediatric care providers by conducting outreach clinics in communities distant from tertiary care centers, with available telephone consultation for acute issues.7,9,74 Regardless, ideally, ongoing close consultation between the pediatric primary care provider and SCD specialist, with a clear delineation of health maintenance responsibilities (to avoid duplication) and rapid access to tertiary care facilities in the event of severe complications, is ideal. In some cases, pediatric primary care providers may need to advocate with managed care organizations or other payers for patients to have access to the SCD team, pediatric hematologist, and other subspecialists.
Patient and Family Education
NBS for hemoglobinopathies supports a diagnosis of SCD before symptoms develop and provides the opportunity for education to allow for a reduction in early complications and mortality. The focus of initial education includes the genetics of the disorder (including that SCD will not go away, trait status of parents and siblings, and availability of prenatal diagnosis, including assisted reproductive technologies for subsequent pregnancies), basic pathophysiology of SCD, and the importance of regularly scheduled general and SCD-specific health care maintenance visits. The rationale for penicillin prophylaxis and immunizations (including additional pneumococcal and meningococcal vaccines) is based on the specific diagnosis. It is key that education about and planning for (including location and how to access) urgent medical evaluation for febrile illness (potential bacteremia), pallor (potential exaggerated or accelerated anemia due to hyperhemolysis or acute splenic sequestration, transient aplastic crisis), and/or difficulty breathing (potential severe anemia, acute chest syndrome) be developed early and reviewed at each visit. A significant component of the education concerns the specific SCD diagnosis (HbSS, HbSC, Sβ0-thalassemia, or Sβ+-thalassemia) and the unique spectrum of complications most common to that disorder.
In adolescence, the focus of the education changes from the family to the patient; addressing general SCD education, past personal complications, management of acute problems, use of nonpharmacologic pain management approaches, as well as potential organ dysfunction and the importance of regular medical follow-up. Painful events appear to be more common around menstruation, and education about distinguishing dysmenorrhea from generalized sickle cell pain may be helpful.75,76 Genetic counseling and carrier testing of partners; prenatal diagnosis; assisted reproductive technologies, including in vitro fertilization with preimplantation genetic testing; contraception; as well as education, career, and insurance issues for adulthood are also discussed. The goal is to aid the patient and family in recognizing that SCD is a treatable condition that requires attention and active management to achieve optimum life outcomes. Peer education and role models are invaluable for successful adolescent transition to adulthood; patient and family engagement with community-based organizations and online support groups should be encouraged.
Health Maintenance
Comprehensive Medical Evaluations
A sickle cell comprehensive visit includes assessment of hematologic values, review of prior disease manifestations, and physical examination with emphasis on growth and general, as well as neurologic, development. Blood pressure values are carefully reviewed according to age-specific norms, given that values for persons with SCD may be lower than hematologically normal individuals.6,77,78 Oxygen saturation is evaluated noninvasively and tracked over time. The presence of a palpable spleen is determined and family member education about home daily spleen palpation is reinforced. School performance is monitored by parents, teachers, and all members of the health care team (both generalist and specialist).14 If academic or neurodevelopmental problems are suspected, assessment including brain MRI/MRA for silent cerebral lesions (common in HbSS) and neurocognitive testing may be warranted.54 Assistance will be needed in pursuing available educational accommodations such as a 504 plan and/or an individualized education program, to optimize learning. For preschool-aged children with developmental delay, referral to local early childhood intervention programs is indicated.79
Age-specific screening for disease complications is a component at all SCD comprehensive visits: For example, stroke risk evaluated by transcranial Doppler ultrasonography in HbSS and Sβ0-thalassemia starting at age 2, as well as dilated fundoscopic examination for retinopathy and urinary protein evaluations annually starting at age 10 years, for persons with all genotypes.6 Some groups have recommended a single, nonsedated MRI of the brain for early school-aged children, because poor academic performance may not be a sensitive or specific indicator of SCD-related brain events.54,61 Imaging will ideally occur using the published parameters for silent cerebral infarct and interpreted by neuroradiologists familiar with the cerebrovascular manifestations of SCD.
If recurrent or persistent pain is an issue, consultation with palliative care or physical medicine services is valuable. This is also a good opportunity to again review interventions to ameliorate SCD (eg, hydroxyurea and other medications, hematopoietic stem cell transplantation or gene therapy, or chronic transfusion), with specific reference to an individual child and their disease course. If the patient is on disease-modifying therapy, adherence is reviewed, as well.
Immunizations
All routine childhood immunizations, including the pneumococcal conjugate vaccine (PCV) series, SARS-CoV-2, and annual inactivated influenza vaccine, as recommended by the American Academy of Pediatrics, are essential, because persons with SCD are considered to be at high risk because of functional asplenia.80 However, the extent of splenic dysfunction in the absence of surgical splenectomy varies by genotype (with HbSS and HbSβ0-thalassemia having the earliest and most profound splenic dysfunction). The 2023 recommendations of the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (CDC) are a complete PCV series (using either 15-valent [PCV15] or 20-valent [PCV20]) for children with all forms of SCD, with catch-up dosing through 71 months of age. For children 6 to 18 years of age who received all recommended doses of PCV before age 6 years (including at least 1 dose of PCV20), no additional doses of any pneumococcal vaccine are indicated. If no dose of PCV20 was received (all prior doses being 13-valent PCV or PCV15), 1 additional dose of PCV20 or 23-valent pneumococcal polysaccharide vaccine is recommended. For children 6 to 18 years of age with SCD who have not received any doses of PCV (13-valent PCV, PCV15, or PCV20), a single dose of PCV15 or PCV20 is recommended. If PCV15 is used, it should be followed by a dose of 23-valent pneumococcal polysaccharide vaccine at least 8 weeks later (if pneumococcal polysaccharide vaccine has not been previously given).81 As recommendations for PCV use are evolving rapidly because of introduction of newer vaccines, it is always advisable to consult the relevant sections of the Red Book and the most up-to-date immunization schedule.82–85 The CDC offers PneumoRecs VaxAdvisor, a free customizable vaccination recommendation app that is useful in confirming the vaccines a partially immunized patient may require.84 Meningococcal conjugate vaccine is given at a young age against serotypes A, C, W, and Y and after age 10 years for serotype B, per recommendations for children with functional asplenia with subsequent boosters.80,82,86 Current recommendations for timing of all vaccines should be consulted before administration.82,83
Prophylactic Medications
Penicillin V potassium prophylaxis, 125 mg orally, twice a day, by 2 months of age, is indicated for all infants with HbSS and Sβ0-thalassemia. The dose is increased to 250 mg orally, twice a day, at 3 years of age and continued until age 5 years or the pneumococcal vaccine series is completed.80,82,83,85 Continuation of prophylactic penicillin V after the fifth birthday may be appropriate in selected patients, including those with a history of invasive pneumococcal infection or surgical splenectomy.23,29,80,85 Routine penicillin prophylaxis for children with HbSC and Sβ+-thalassemia, in the absence of surgical splenectomy, is not generally recommended.6,80,87,88 Amoxicillin, 20 mg/kg/day, is sometimes substituted for penicillin based on medication cost or taste,80 although crushed penicillin tablets given in a small volume of liquid may offer an advantage in terms of cost and the need for biweekly refills.6 An alternative for children with penicillin allergy is erythromycin. Adherence with, and the rationale for, antibiotic prophylaxis is reviewed at every medical contact. Folic acid supplementation, given the widespread supplementation of formula and grain products in the western world, is no longer needed.6,89
Disease-Specific Treatments
In addition to prophylactic penicillin, there are SCD-specific treatments aimed at either modifying or curing the disease. Hydroxyurea is the first agent recommended and the one with which there is the greatest length of experience, particularly in children. In time, a multiagent approach will likely become more common.90 Hydroxyurea increases total and fetal hemoglobin and decreases vaso-occlusive complications including episodes of painful events and acute chest syndrome, hospitalizations, and need for transfusion.91,92 The National Heart, Lung, and Blood Institute-funded Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) demonstrated that hydroxyurea is of significant benefit presymptomatically to infants with HbSS or Sβ0-thalassemia and has no unique adverse effects, even if initiated in early infancy and continued for more than a decade.93,94 Hydroxyurea use has a positive impact on health-related quality of life in people with HbSS or Sβ0-thalassemia.72 The 2014 National Heart, Lung, and Blood Institute guidelines for SCD recommend offering hydroxyurea to every child with HbSS or Sβ0-thalassemia at 9 months of age even without clinical symptoms.6 Hydroxyurea is taken once a day orally and is supplied as a capsule, fast-dissolving tablet, or compounded liquid. Myelosuppression is a potential adverse effect; a CBC and reticulocyte count is monitored every 1 to 3 months depending on how long the child has been taking the medication and whether the child has attained a stable dose.6
L-glutamine (Endari)* may reduce the number of pain events in children 5 years and older.95 The mechanism of action is poorly understood, but L-glutamine may regulate nicotinamide adenine dinucleotide + hydrogen/total nicotinamide adenine dinucleotide in red blood cells, decreasing the oxidative stress and, thus, hemolysis. It comes as a powder packet that is mixed in liquid or food twice daily. It does not require laboratory monitoring.
Crizanlizumab, a monoclonal antibody P-selectin inhibitor, blocks adhesion of blood elements to endothelial cells and thus may decrease vaso-occlusion. It is approved for persons 16 years of age and older to decrease the frequency of hospitalization for painful events.96 It is administered as an intravenous infusion every 4 weeks after two infusions two weeks apart.
Voxelotor, an HbS polymerization inhibitor, increases the affinity of hemoglobin for oxygen and thus decreases HbS polymerization. This results in a mean 1 g increase in hemoglobin.97 It is approved for children and adults 4 years and older. It is a tablet, or tablet for oral suspension, taken orally once daily.
To prevent the development of some complications of SCD, monthly red blood cell transfusions may be given to suppress the bone marrow and decrease HbS percentage.27,28 Transfusion is most commonly prescribed for children who are at high risk of developing stroke or who have already developed a stroke (primary or secondary stroke prophylaxis).6,57–59 Transfusion is also prescribed for select children with recurrent complications who do not respond to other disease-modifying therapies. The potential adverse effects include febrile and allergic reactions, transmission of pathogens, alloimmunization, and iron overload. In addition, some children may require an indwelling central line, which has an associated risk of infection and thrombosis.6,27,28 After 12 to 20 transfusions, children will require iron chelation therapy to treat iron overload.
Hematopoietic stem cell transplantation has been used as a curative treatment of SCD for almost 4 decades. Best outcomes are achieved when the donor is an HLA-matched sibling and the procedure occurs before 16 years of age.98,99 Because many patients lack an HLA-matched sibling, alternative donors have been used but have been limited by adverse effects. The main adverse effects include infection, graft rejection, and graft-versus-host disease. Infertility is also a risk, especially with myeloablative transplant regimens.
SCD is a single-gene disorder, making it an ideal candidate for gene therapy. Ongoing clinical research is studying 3 different approaches: (1) gene addition, (2) gene correction, and (3) gene editing to promote fetal hemoglobin induction. Current techniques require harvesting patient’s own stem cells, modifying those cells in the laboratory, then eradicating patient’s remaining bone marrow cells with chemotherapy followed by infusion of the genetically modified stem cells.100 Although 2 commercialized approaches received US Food and Drug Administration approval in December 2023, the risks and long-term benefits of gene therapy still require investigation.
Psychosocial Care
Comprehensive care includes periodic psychosocial assessments and access to services needed to optimize the patient’s and family’s adaptation to chronic illness.6,8 Children with SCD with higher levels of parental support report less depressive symptoms and better quality of life, emphasizing this key component of care.101 Personal and cultural beliefs about illness and existing stresses and support systems may greatly impact the ability to cope with SCD.102 Extended family networks can provide an important support system for parents of children with SCD.103 Patient support groups and community-based organizations can be important resources. Extended members of a dedicated sickle cell specialist team, such as nurse practitioners, physician assistants, nurse specialists, nurses, social workers, therapists, clinic navigators, and educational liaisons, can be vital in mentoring, supporting academic achievement, and ensuring that all patients receive information about best medical practices.14 Relevant issues to discuss include health insurance coverage, transportation for health care, and education of peers and school personnel about SCD.6–9
Genetic Education and Counseling
The pediatrician or other pediatric primary care provider may be involved in the counseling of a patient or couple at risk for having a child with SCD. Education includes a review of autosomal recessive inheritance and the provision of accurate information about genetic risk and the clinical course of disease and trait, medical complications, and treatment of the specific SCD genotype relevant to the family.16,20–22,26,68 Genetic risk cannot be assumed from the diagnosis of SCD in a previous child or from the family’s memory of test results; documentation of parental testing is essential. Such testing includes a CBC and hemoglobinopathy testing (as described previously). Solubility testing (such as SickleDex) is not adequate and is not recommended for carrier testing, because it will not identify individuals with hemoglobin C or β-thalassemia trait.
It is important that adolescents with SCD receive accurate information16,20–22,26,68,104 about:
Genetic transmission of SCD—1 gene from each parent results in disease.
Availability of carrier testing for partners—all offspring of a person with SCD will have at least 1 gene for SCD; the trait status of the partner will determine possibility of child with SCD.
Prenatal diagnosis—availability of testing of fetus for SCD before birth (amniocentesis, chorionic villous sampling, or preimplantation genetic diagnosis), as well as assisted reproductive technologies including in vitro fertilization and preimplantation genetic diagnosis.
Planning pregnancies—knowing the SCD or trait status of both partners.
Contraception—levonorgestrel-releasing intrauterine device, depot medroxyprogesterone acetate injection, etonogestrel implant, and progestin-only oral contraceptive pills are preferred because of an increased risk of thrombosis in SCD, but for specific patients, combined low-dose estrogen or combined oral contraceptive pills, nonhormonal, or barrier methods may be preferred, particularly as backup contraception or for prevention of sexually transmitted infections. Method advised is unique to each patient circumstance and preference.105–107
Effects of current medications on fertility and/or pregnancy.108
When an adolescent with SCD becomes pregnant, comanagement by a hematologist with expertise in SCD and a high-risk obstetrician is essential. Pregnancy is often associated with an increased frequency of SCD complications,109 but most pregnancies in people with SCD have a successful outcome for the parent and infant.
Transition
Transition from a pediatric to adult care model requires a structured but flexible process designed to address the intricacies of SCD. Historically, it has been a time of increased emergency department visits, hospitalizations, and mortality, likely because transfer rather than transition has occurred.110,111 Successful transition requires self-efficacy and advocacy on the patient’s part, as well as communication between the pediatric and adult primary care and specialty providers.112,113 Insurance planning is critical, and discussions must begin in the mid-teen years. It also requires parental and community support, along with the identification of mental health and cognitive barriers.
Specific information about the transition of patients with SCD from pediatric to adult care can be found from various sources.114,115 Special care must be taken to identify a site of both acute and ongoing care for college-bound students at home and at school, as well as a source of reproductive health care (specifically gynecology) from providers knowledgeable about SCD. There are many Internet-based resources to facilitate transition, including the Sickle Cell Transition E-learning Program (from St Jude Children’s Research Hospital116 ), Got Transition from the Maternal and Child Health Bureau,117 and Taking Charge of Your Health and Health Care plan from the CDC.118 Generally, knowledge in medical, social, and employment/academic domains is an expectation for readiness to transition. The American Society of Hematology has a sickle cell transition readiness assessment tool and resources available online.119
Health Supervision From Birth to Early Adulthood
Improvements in care have resulted in almost all children with SCD surviving into adulthood and transitioning into adult care, which has allowed shifting the goal of care to improved quality of life. Optimal care does not occur in isolation but requires comanagement between the pediatric primary care provider and hematology specialist team. Psychosocial support is important throughout the age span, and availability of online resources is increasing. Tables 2 and 3 review the care of children with SCD from birth through transition (by age group), with an emphasis on health maintenance and education (patient and family), respectively.
Lead Authors
Amber M. Yates, MD, FAAP
Banu Aygun, MD, FAAP
Rachelle Nuss, MD, FAAP
Zora R. Rogers, MD, FAAP
Section on Hematology/Oncology Executive Committee, 2022–2023
Cynthia Wetmore, MD, PhD, FAAP, Chair
David Dickens, MD, FAAP
Suvankar Majumdar, MD, FAAP
Zora R. Rogers, MD, FAAP, Immediate Past-Chair
Jayson Stoffman, MD, FAAP
Anne Warwick, MD, MPH, FAAP
Amber Yates, MD, FAAP
Irtiza Sheikh, DO, FAAP
Partnership for Policy Implementation
Eneida A. Mendonca, MD, PhD, FAAP, FACMI
Jeremy J. Michel, MD, MHS, FAAP
Staff
Suzanne Kirkwood, MS
American Society of Pediatric Hematology/Oncology Board of Trustees, 2022–2023
Doug Graham, MD, PhD (President)
Caroline Hastings, MD (Vice President)
Jorge DiPaola, MD (Immediate Past President)
Jeffrey Hord, MD, FAAP
Sarah Alexander, MD
Winston Huh, MD
Michael Jeng, MD
Maria Velez, MD
Dan Wechsler, MD, PhD
Staff
Ryan Hooker, MPT
Endari is the only formulation of L-glutamine approved by the US Food and Drug Administration for the reduction of pain events in people with SCD. This is not an endorsement by the American Academy of Pediatrics.
Dr Rogers developed the concept for the format of this report, researched and wrote individual sections, edited the draft, and rewrote sections in response to internal American Academy of Pediatrics and external group reviews; Dr Aygun researched and wrote individual sections, edited the draft, and rewrote sections in response to internal American Academy of Pediatrics and external group reviews; Dr Nuss researched and wrote individual sections, edited the draft, and rewrote sections in response to internal American Academy of Pediatrics and external group reviews; Dr Yates researched and wrote individual sections, and wrote the first complete draft; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication.
Clinical reports from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and external reviewers. However, clinical reports from the American Academy of Pediatrics may not reflect the views of the liaisons or the organizations or government agencies that they represent.
The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.
All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.
FUNDING: No external funding.
FINANCIAL/CONFLICT OF INTEREST DISCLOSURE: Dr Nuss has disclosed a relationship as an investigator with Editas Ruby trial. Dr Yates has disclosed a financial relationship as an employee with Agios Pharmaceuticals. Dr Rogers has disclosed a financial relationship as the chair of the data monitoring committee with Novartis, a financial relationship as a member of the endpoint adjudication committee with IQVIA RDS IQVIA, a financial relationship as a panel member with Phar Inc., a financial relationship as a working group member with RTI, a financial relationship as an author with Up to Date, a financial relationship as a panel member with Leidos, and a financial relationship as a panel member with NHLBI. Disclosures are reviewed and mitigated through a Conflict of Interest process approved by the AAP Board of Directors.
- CBC
complete blood cell count
- CDC
Centers for Disease Control and Prevention
- HbS
hemoglobin S
- HbSC
sickle hemoglobin C disease
- HbSS
sickle cell anemia
- MRA
magnetic resonance angiography
- NBS
newborn screening
- PCV
pneumococcal conjugate vaccine
- PCV15
15-valent pneumococcal conjugate vaccine
- PCV20
20-valent pneumococcal conjugate vaccine
- SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
- SCD
sickle cell disease
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