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INTRODUCTION

Vaso-occlusive phenomena and hemolysis are the clinical hallmarks of sickle cell disease (SCD) that can cause many clinical manifestations.

  • Vaso-occlusion can cause recurrent painful episodes that can lead to chronic pain and serious organ function decline, which can result in life-long disabilities and even death. Splenic infarction with functional asplenia increases the risk of serious infections.
  • Hemolysis causes chronic anemia and pigment gallstones and releases free hemoglobin, which reduces nitric oxide bioavailability and generates harmful metabolites like heme. Along with vaso-occlusion, these processes can contribute to end-organ complications of SCD.

This topic review discusses general principles of preventive/outpatient care in patients with SCD, including infection prevention, nutrition, travel advice, and routine evaluations and preventive interventions.

Separate topics discuss:

  • Advice for general pediatric care
  • Transition from pediatric to adult care
  • Management during hospital admission
  • Obstetric management
  • Disease-modifying therapies
  • Curative therapies
  • Treatment of complications
  • Acute chest syndrome
  • Bone and joint complications
  • Cerebrovascular disease
  • Children
  • Fever
  • Hepatic disease
  • Pain
  • Priapism
  • Pulmonary complications
  • Pulmonary hypertension
  • Kidney manifestations
  • Transfusional iron overload

GENERAL PRINCIPLES AND GUIDELINES

Relationship of trust — Beyond the technical screening and treatment of medical problems, the primary physician and other clinicians involved in the individual’s care should build a trusting relationship that allows for:

  • Sharing of new medical information
  • An environment where the individual with SCD and family/caregivers can voice their concerns about the future and their treatment including:
  • Discrimination
  • Stigma
  • Depression
  • Sleep disturbances
  • Neurocognitive difficulties
  • Infertility
  • Chronic organ failure
  • Medication adherence
  • Risks of future morbidities
  • Risks and benefits of evolving therapies

It is necessary to allocate adequate time for an individualized pain plan and for discussions about these and other sensitive subjects.

This is especially important during the transition from pediatric to adult care, which is a critical time for patients with SCD.

Comprehensive health care maintenance — Individuals with SCD should be seen regularly by the clinician and treatment team, ideally as part of a comprehensive health care maintenance program, recognizing that most adults in the US are not cared for in a specialized center .

Routine office visits are used to educate the individual and family/caregivers about SCD, infection prevention, pain management strategies, and anticipatory guidance for possible complications (eg, splenic sequestration, avascular necrosis of the femoral head, stroke, leg ulcers).

Education regarding the nature of the disease, genetic counseling, and psychosocial assessments of individuals and their families/caregivers are also best accomplished during these visits, reinforced, when possible, with telephone-based outreach programs.

In addition, obtaining steady-state laboratory values (hemoglobin, reticulocyte count, white blood cell count, and pulse oximetry readings) during routine visits will provide standards for comparison during clinical exacerbations, because these values are often abnormal at baseline.

A comprehensive healthcare maintenance program for SCD individuals should include the components discussed below

Disease-modifying and curative therapies — All individuals with SCD should have regular opportunities to discuss medical therapies to ensure they understand the benefits and risks and are able to incorporate their values and preferences into decision-making. Patients and families/caregivers should be made aware of open trials that would be beneficial to the patient. Sufficient time should be allocated to answer their questions.

The major disease-modifying therapies include:

  • Hydroxyurea– Hydroxyurea is the mainstay of SCD management.

It reduces the incidence of acute vaso-occlusive events including pain episodes, acute chest syndrome, and in some cases stroke. Hydroxyurea decreases hospitalization rates and prolongs survival.

  • Other medications– Other medications to reduce vaso-occlusive complications are available (and more are under investigation) if hydroxyurea is ineffective or cannot be tolerated. These therapies can also be used in combination with hydroxyurea, provided hydroxyurea is providing benefit but vaso-occlusive episodes continue.
  • Transfusions – Blood transfusions are used in the following settings:
  • Before surgery
  • To treat symptomatic anemia, acute stroke, multiorgan failure, and acute chest syndrome
  • To reduce the risk of stroke

The main benefit comes from reducing the percentage of sickle hemoglobin. Increasing the hemoglobin may be beneficial in some cases, but raising the hemoglobin too high risks hyperviscosity. These indications, along with practical aspects of central venous access, crossmatching, leukoreduction, simple versus exchange transfusion, and management of excess iron stores, are discussed separately.

  • Curative therapies– Allogeneic hematopoietic stem cell transplantation or autologous transplantation with gene therapy can cure or substantially modify the disease course of SCD. All individuals should have the opportunity to review these options with a trusted clinician, with the understanding that discussing this information does not obligate the individual to pursue curative therapy.

Evidence base and guidelines — Evidence-based recommendations for the management of SCD were published in 2014 by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) and endorsed by a number of societies including the American Academy of Pediatrics (AAP) and the American Society of Hematology (ASH); these are available on the NHLBI website and in summary form.

In 2020, ASH published additional guidelines and other resources (ASH guidelines). Recommendations are largely consistent with those presented here.

A Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/ncbddd/sicklecell/index.html) also provides information on SCD [8].

INFECTION PREVENTION

Overview — Individuals with SCD are at increased risk of bacterial and viral infections, largely due to functional asplenia that develops early in childhood (later in individuals with less-severe SCD syndromes). Their clinical course from these infections is often more severe than individuals without SCD.

  • The two principal measures for preventing infection in individuals with SCD are appropriate immunizations for all children and adults, and prophylactic penicillin for all young children (<5 years of age, sometimes older.
  • When feasible, vaccination and/or antibiotic prophylaxis may be indicated for individuals with SCD who are household contacts of persons with certain infections.
  • Fever is a medical emergencyrequiring prompt medical attention, blood cultures, and treatment with antibiotics. Parents and caregivers of infants and children with SCD should also be instructed regarding early recognition of infection, which may present with isolated fever. A formal plan should be created for seeking medical attention for a predetermined elevated temperature (>38.5°C or >101.5°F), and a strategy should be discussed regarding plans in case a fever develops during travel or when visiting with family members or caregivers who may not be familiar with the routine. Adults should also have a clear plan for seeking medical attention for signs of infection. This important issue is discussed separately.

Functional asplenia is presumed to exist in individuals with Hb SS and Hb S-beta0 thalassemia within the first year of life. It can be identified by Howell-Jolly bodies on the blood smear.

Immunizations — Immunizations are a cornerstone of infection prevention in SCD. A review of the patient’s immunizations should be performed at every medical contact to ensure that they are up to date.

Children with SCD should receive all routinely recommended childhood vaccines, including those for COVID-19, Streptococcus pneumoniae, seasonal influenza, Neisseria meningitidis, Haemophilus influenzae type B, and hepatitis B virus.

  • COVID-19– People with SCD have increased morbidity and mortality from COVID-19. COVID-19 vaccination (including booster doses) is recommended. Significant antibody responses have been reported.
  • Pneumococcal disease– Vaccination has led to a decrease in the incidence of invasive pneumococcal disease in children with SCD [14,18,19]. In the United States, a 13-valent, 15-valent, and 20-valent pneumococcal conjugate vaccine(PCV), and a 23-valent pneumococcal polysaccharide vaccine (PPSV23) are available.

The PCV can be administered as early as six weeks of age and elicits an effective immunologic response during the first two years of life. The pneumococcal polysaccharide vaccine (PPSV23) includes a greater number of serotypes but is not immunogenic in children <2 years of age. Penicillin prophylaxis does not appear to interfere with an IgG response to immunization [12].

Vaccination recommendations have changed with the introduction of the PCV20 vaccine; this is because individuals who have received PCV20 do not require PPSV23 (previously, those who received PCV13 or PCV15 did require PPSV23). Details are discussed separately, including:

Choice of influenza vaccine for children

Table 2

Analysis of the Healthcare Cost and Utilization Project (HCUP) 2003 to 2005 state inpatient data indicated that although children with SCD were hospitalized for influenza 56 times more often than those without SCD, neither the length nor cost of hospitalization differed [21]. Therefore, effective influenza vaccination may decrease the hospitalization rate by decreasing the number of febrile episodes that require evaluation and treatment. (See “Prevention of infection in patients with impaired splenic function”, section on ‘Vaccinations’.)

Meningococcal vaccination recommendations for children age 2 through 23 months who are at increased risk of meningococcal disease in the United States[1,2]

Table 3

Meningococcal vaccination recommendations for persons age ≥2 years who are at increased risk of meningococcal disease in the United States[1-3]

Table 4

Data from a large randomized trial of hydroxyurea use (the BABY HUG trial) are reassuring that the use of hydroxyurea does not interfere with the response to immunizations [22]. (See “Hydroxyurea use in sickle cell disease”, section on ‘Evidence for efficacy’.)

Most of these vaccinations should be updated periodically during adulthood, according to the recommendations of the Centers for Disease Control or other national regulatory agency. Inactivated virus vaccines are preferred. (See “Standard immunizations for nonpregnant adults”.)

Prophylactic penicillin — Prophylactic penicillin should be given to all individuals with SCD at least until age five [6,23]. Parents/caregivers of young children should confirm that prophylactic penicillin is being used appropriately.

  • Before age five years– The dose from age three months to three years is 125 mg penicillin Vorally twice daily, and at age three years this should be increased to 250 mg twice daily until the age of five years [24,25]. (See “Prevention of infection in patients with impaired splenic function”, section on ‘Antibiotic prophylaxis’.)
  • After age five years– After the age of five years, some parents/caregivers, with consultation of their clinicians, elect to stop penicillin prophylaxis, while others will continue [26]. This is an important issue given the lifelong persistence of splenic dysfunction starting in late childhood and continuing through adulthood.

Many pediatric clinicians elect to stop prophylaxis if the child has not had a prior severe pneumococcal infection or splenectomy and is receiving comprehensive care, including vaccination with the pneumococcal polysaccharide vaccine (PPSV23) [6,26]. However, others will continue penicillin prophylaxis through adulthood because of the lifelong risk of pneumococcal infection, including infection with pneumococcal disease with serotypes not included in the vaccines [27].

The benefit of prophylactic penicillin has been demonstrated in two large randomized trials [28,29]. A 2012 Cochrane review of these trials included data from 457 patients with SCD [30]. As compared with no treatment or placebo, penicillin prophylaxis was associated with a decreased risk of pneumococcal infection (odds ratio 0.37, 95% CI 0.16-0.86) and a decreased risk of death (odds ratio 0.11, 95% CI 0.01-2.11). Adverse effects were minimal. Further discussion of these trials and related issues, such as penicillin resistance and country-specific guidelines, is presented elsewhere. (See “Prevention of infection in patients with impaired splenic function”, section on ‘Antibiotic prophylaxis’.)

A randomized trial evaluated the safety of stopping penicillin prophylaxis in 400 children with SCD who had received penicillin prophylaxis for at least two years immediately before their fifth birthday and had received the 23-valent pneumococcal vaccine between two and three years of age, and again at the time of randomization (optimal prophylaxis) [25]. The incidence of systemic pneumococcal infection during 3.2 years of follow-up was very low and not significantly different in those receiving placebo or continued penicillin prophylaxis (2 versus 1 percent).

Pneumococcal sepsis does occur in children taking penicillin who have received the pneumococcal vaccine, and factors affecting adequacy of pneumococcal prophylaxis should be explored [31,32]. As an example, publicly insured children with SCD often receive inadequate antibiotic prophylaxis. In a review of Washington State and Tennessee Medicaid programs, the average prescription for prophylactic antibiotics for individuals with SCD was for only 148 days of medication per year [33]. Efforts to improve penicillin access should be pursued. (See “Evaluation and management of fever in children and adults with sickle cell disease”.)

Hb SC disease and sickle cell-beta thalassemia — Compared with patients with hemoglobin (Hb) SS, those with certain compound heterozygous SCD syndromes (Hb SC disease, sickle cell-beta thalassemia) may have reduced susceptibility to serious infections, depending on their disease severity and remaining splenic function. (See “Overview of compound sickle cell syndromes”.)

  • Hb SC– Individuals with Hb SC disease are less likely to develop invasive bacterial infection than those with Hb SS [34-36]; this is because they maintain some splenic function during early childhood [37]. Individuals with Hb SC disease who develop bacteremia are less likely to develop sepsis and septic shock or to die from sepsis [34,36,38]. While routine childhood immunizations and a clear plan for seeking medical therapy for any febrile episode are important, individuals with Hb SC disease are not routinely prescribed prophylactic penicillin [36]. (See “Overview of compound sickle cell syndromes”, section on ‘Hb SC disease’.)
  • Sickle cell-beta thalassemia– Among individuals with sickle cell-beta thalassemia, severity of the disease varies with the production of Hb A, and management varies accordingly. (See “Overview of compound sickle cell syndromes”, section on ‘Sickle-beta thalassemia’.)
  • Patients with sickle cell-beta0thalassemia (Hb S-beta0thalassemia) have a clinical course similar to patients with Hb SS disease, with development of functional asplenia early in childhood and a similar risk of invasive bacterial infection. As a result, their infection prevention strategy should be the same as those with Hb SS, including immunizations, prophylactic penicillin, and empiric antibiotic therapy when they are febrile.
  • Patients with sickle cell-beta+thalassemia (Hb S-beta+thalassemia) produce variable amounts of Hb A and in general have less severe SCD complications, although limited data are available regarding their risk of infection [36]. In general, they are treated in a manner similar to those with Hb SC disease.

Functional asplenia can be identified in these individuals by Howell-Jolly bodies on the blood smear. (See “Evaluation of the peripheral blood smear”, section on ‘Howell-Jolly, Heinz, and Pappenheimer bodies’.)

NUTRITION

There are few prospective data regarding the clinical benefit of nutritional interventions that can be used to guide nutritional management in patients with SCD. Growing evidence suggests that individuals with SCD have vitamin and micronutrient deficiencies that may influence the course of their disease [39-44].

Folic acid is often prescribed to individuals with SCD in an oral dose of 1 mg daily. However, some clinicians may reasonably omit folic acid supplementation for patients with sufficient dietary intake, especially in settings where grains and cereals are routinely supplemented.

Despite the rationale of increased folate requirements from ongoing hemolytic anemia, there are no data that folic acid supplementation reduces anemia in individuals with SCD.

A 1983 randomized trial of folic acid supplementation in 117 children with SCD showed that compared with controls, those receiving folic acid did not show an improvement in hemoglobin levels or growth characteristics but did have a decrease in mean cell volume and less dactylitis [46]. A 2025 randomized crossover trial of folic acid versus placebo in 31 children with SCD also did not show clinically significant differences in hemoglobin values or vaso-occlusive pain [49]. Despite this, we believe that the potential yet unknown benefit from folic acid supplementation outweighs the potential harms.

During pregnancy, higher doses of folic acid (eg, 4 mg daily) are used to provide sufficient folates for ongoing hemolysis as well as embryonic/fetal development. (See “Preconception and prenatal folic acid supplementation”, section on ‘Maternal medical conditions that reduce folic acid availability or activity’.)

  • Multivitamin– We use a daily multivitamin withoutiron for all individuals with SCD. This replaces some of the vitamins and micronutrients commonly reported to be deficient in these individuals, including zinc, vitamin D, vitamin E, vitamin C, vitamin A, magnesium, selenium, carotenoids, and flavonoids, although the benefits of taking a multivitamin have not been examined in randomized trials [39-42]. Excess iron stores (from chronic or intermittent transfusions) and oxidative injury may contribute to the depletion of antioxidant vitamins.
  • Selected individuals – Screening for other nutrient deficiencies, especially vitamin D and iron, is discussed below. (See ‘Routine evaluations and preventive interventions’below.)

Additional supplementation is used for individuals with documented deficiencies.

A 2024 study treated 42 children with SCD and 42 matched controls with high-dose oral monthly vitamin D3 (100,000, 150,000, or 200,000 international units, depending on vitamin D status) and noted reductions in pain and improvements in DXA (dual-energy x-ray absorptiometry) score and other parameters [50]. The SCD group had lower baseline vitamin D levels compared with controls (17 versus 28 ng/mL) and reduced growth status.

Observational studies have also demonstrated that most children with SCD have vitamin D deficiency and inadequate calcium intake [51,52]. These deficiencies may contribute to osteopenia and osteoporosis, which affect up to 80 percent of patients with SCD. (See “Acute and chronic bone complications of sickle cell disease”, section on ‘Osteopenia and osteoporosis’.)

There is also an incompletely understood relationship between vitamin D deficiency and chronic pain in children with SCD [52,53]. In the vitamin D supplementation study, erythrocyte sedimentation rate (ESR) decreased with vitamin D supplements, suggesting possible reduced inflammation [50]. (See “Disease-modifying therapies to prevent pain and other complications of sickle cell disease”, section on ‘Overall health maintenance’.)

  • Iron– Iron overload may be more common than iron deficiency in individuals who have received several transfusions. However, iron deficiency can also occur, particularly in young children.

We screen all infants with SCD for risk factors for iron deficiency, including those not receiving transfusions, during the first two years of life. We also use laboratory screening at one year of age, as advised by the American Academy of Pediatrics (AAP). All children with SCD who have evidence of iron deficiency anemia should be treated because iron deficiency has a negative effect on neurodevelopment. (See “Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis”, section on ‘Screening recommendations’.)

Non-transfused individuals with risk factors for iron deficiency also should undergo screening and treatment. In patients with iron deficiency, it is important to establish the cause. (See “Diagnosis of iron deficiency and iron deficiency anemia in adults” and “Determining the cause of iron deficiency in adolescents and adults”.)

Clinical trials have demonstrated significant improvements in growth and bone health as well as reduced infection rates with correction of zinc deficiency [56]. However, most studies are not definitive, and some are conflicting. In addition, the optimal dose to obtain normal levels has not been established. Often, patients remain zinc deficient despite supplementation, complicating study results [57]. Annual monitoring of zinc levels is not a mandatory requirement, and evidence to support the clinical utility of screening zinc levels is lacking; however, we screen zinc levels annually or every two years because of the potential benefits and the known complications in this population.

TRAVEL ADVICE

There are no travel restrictions for individuals with SCD. However, we generally advise individuals with SCD to postpone elective travel if they are ill. In addition to a written travel letter that will facilitate relevant clinical care information and physician contact information, we provide advice regarding planning prior to, during, and after travel, and care at the destination. (See ‘Planning for care away from home’ below and ‘Advice specific to air travel’ below.)

Planning for care away from home — It is important to have a plan should disease complications occur, such as infection (or fever) or vaso-occlusive events (pain, acute chest syndrome). This plan should be discussed with family members and caregivers who may not be familiar with SCD.

Planning can be divided into preparation, during travel, and at the destination:

We often provide a letter for the individual or parents/caregivers to share with local medical services that includes the individual’s diagnosis, contact information for the primary hematologist or on-call coverage, and a list of concerning symptoms with our preferred evaluation and treatment. This includes:

  • Fever >101.4 °F– Aggressive evaluation for the source of fever, including complete blood count (CBC), reticulocyte count, blood culture, urine culture, and chest radiograph, with antibiotics given pending the results (intravenous if toxic-appearing; oral if not toxic-appearing).
  • Acute chest pain or dyspnea– CBC, reticulocyte count, chest radiograph, and possibly arterial blood gas, with antibiotics for fever and hospitalization for severe pain.
  • Neurologic symptoms(seizures, focal findings, severe headache) – Extensive neurologic evaluation including evaluation for ischemic or hemorrhagic stroke; exchange transfusion may be indicated.
  • Acute painnot relieved by usual outpatient measures – Aggressive evaluation for the source, including CBC, reticulocyte count, and other testing, with opioid analgesia given rapidly.
  • Marked lethargy or dehydration– Examination, documentation of spleen size, CBC, reticulocyte count, and electrolytes, with hydration with salinesolution.

Advice specific to air travel — Individuals with SCD can use standard commercial airline travel and should not be discouraged from air travel. Avoid travel in unpressurized aircraft above 5000 feet (increased risk for vaso-occlusive events). The risk for in-flight vaso-occlusive complications on commercial airlines are considered to be low, although evidence is limited.

  • Hydration– Hydration is important; individuals with SCD should have adequate liquid intake to prevent dehydration, which can exacerbate sickling. After passing through airport security, it may be necessary to obtain drinking water or other beverages. Cabin air humidity is very low.
  • DVT risk– Air travel (or other prolonged travel) increases the risk of deep vein thrombosis (DVT), and individuals with SCD should be encouraged to walk around when possible and move their legs, similar to individuals without SCD. (See “Pathogenesis, risk factors, and prevention of venous thromboembolism in adult travelers”.)
  • Oxygenation– Several large case series and our own experience have shown that hypoxic events related to airlines are uncommon [59,60]. We do not advise individuals with SCD to use supplemental oxygen on commercial airline flights, although individuals with SCD can and should request oxygen if they become short of breath during air travel, similar to those without SCD, and those with known hypoxic lung disease or using home oxygen should have oxygen while traveling.

Patients with SCD and pulmonary hypertension are at an increased risk of hypoxic complications; oxygen should be readily available for these individuals [61].

ROUTINE EVALUATIONS AND PREVENTIVE INTERVENTIONS

Interventions and monitoring done by the patient or parents/caregivers — Patients and parents/caregivers can be informed about the importance of the following:

  • Ensuring vaccinations are updated
  • Ensuring medications are available and prescriptions are updated
  • Monitoring spleen size (especially for children or individuals with splenomegaly)
  • Checking the temperature when ill and having a plan to seek assistance if there is a fever
  • Monitoring mental health, often with a patient health questionnaire (PHQ)-9 tool, and seeking support when needed
  • Identifying episodes of priapism and notifying the SCD team (or a trusted member of the team)
  • Being aware of other conditions that may contribute to pain episodes, including stress, gynecologic issues, and others
  • Being aware of school and work performance and notifying the SCD team if there appear to be cognitive or other difficulties

Prevention of splenic sequestration — The natural history of splenic sequestration in infants and toddlers with SCD is well documented, with a reasonable proportion having a second event within 12 months of the first event. In adults with SCD, there are limited data to describe the risk of subsequent splenic sequestration episodes, but in general we would manage them in similar way [62].

  • Future management should include education about self-palpation of the spleen and instructions on what to do in the event of an enlarging spleen.
  • After consideration of risks and benefits, there should be a discussion of the potential removal of the spleen in a non-acute setting.
  • Institution of regular blood transfusion therapy to prevent subsequent episodes of acute splenic episodes is not indicated and has not proven to be of benefit.

Interventions and monitoring done by the medical team — Routine evaluations and associated treatments of individuals with SCD are extensive [1].

While the following list serves as a guideline for screening, it is important to adopt a comprehensive approach that can be followed by the patient. The transition from pediatric to adult providers can be associated with lapses in care, and this is an important time to ensure that routine evaluations have been performed.

  • Hypertension– Blood pressure screening should be done at every visit. Early treatment of systemic hypertension is critical because mild elevations in blood pressure are associated with an increased risk of overt stroke and silent cerebral infarct in individuals with SCD [63,64]. (See “Overview of hypertension in adults”and “Hypertension in adults: Initial drug therapy”.)
  • Cerebral complications
  • TCD screening for stroke risk– In children ≤16 years of age with hemoglobin SS or hemoglobin S-beta thalassemia that produces no hemoglobin A, (Hb S-beta0thalassemia), cerebral blood flow should be evaluated by transcranial Doppler (TCD) annually, because children at risk for strokes can be identified with this technique and the incidence of stroke can be reduced by the use of regular blood transfusion therapy aimed at maintaining the maximum Hb S level at less than 30 percent [65].

In contrast, children with Hb S-beta+ thalassemia and Hb SC disease do not require TCD screening, although screening may be appropriate in those with hemolysis similar in magnitude to Hb SS [23]. In the United States, appropriate TCD screening appears to be decreasing, and obstacles must be overcome to improve screening rates [66]. (See “Prevention of stroke (initial or recurrent) in sickle cell disease”, section on ‘Risk assessment for first stroke’.)

TCD measurements should be started at two years of age and performed annually through age 16 years [6]. Serial TCD screening is recommended because normal flow velocity on a single screening does not assure a continued low-risk status. Individuals with abnormal velocity on TCD should be seen by a specialist with expertise in chronic transfusion therapy and stroke prevention.

These subjects are discussed in detail separately. (See “Prevention of stroke (initial or recurrent) in sickle cell disease”, section on ‘Prevention of a first ischemic stroke (primary stroke prophylaxis)’ and “Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications”, section on ‘Primary and secondary stroke prevention’.)

TCD measurements are lower in adults with SCD compared with children, and there is no evidence to suggest that TCD velocities are predictive of stroke risk in adults. We do not recommend TCD screening in individuals >16 years of age [67,68]. (See “Prevention of stroke (initial or recurrent) in sickle cell disease”, section on ‘Risk assessment for first stroke’.)

The definition of a silent cerebral infarct-like lesion is a signal abnormality on magnetic resonance imaging (MRI) of at least 3 mm in dimension and visible on two planes on fluid-attenuated inversion recovery (FLAIR) or T2-weighted images (or similar images with three-dimensional imaging) with no correlative neurologic findings.

We use MRI evaluation, consistent with the 2020 American Society of Hematology (ASH) recommendations for at least a one-time MRI screening, without sedation, to detect silent cerebral infarcts in early school-age children in whom MRI can often be performed without sedation [69]. MRI is often obtained when care is transferred to the adult SCD team. (See “Sickle cell disease (SCD) in adolescents and young adults (AYA): Transition from pediatric to adult care”, section on ‘Health care transition as a vulnerable time’.)

In high-risk individuals, such as those with major school difficulties or signs of neurocognitive dysfunction, detailed neurocognitive testing is advised.

Adults may have progressive neurocognitive injury that may not be detected without a formal protocol. In addition, screening for health literacy and activities of daily living are recommended [70]. If health literacy and activities of daily living are impaired, neuropsychological testing is appropriate, and neurocognitive remediation programs may be indicated. As patients age, preliminary data suggest they are at risk for premature dementia. The Rowland Universal Dementia Assessment Scale (RUDAS) was specifically designed for cognitive screening [71]. The RUDAS evaluates executive function, memory, language, and perceptual-motor function. It was designed to minimize educational bias and can be administered in six minutes. Use of the RUDAS in adults with SCD documented scores consistent with dementia in 29 of 252 participants (12 percent); the proportion increased with age, up to 15 percent in the 40 to 59 years age group and 36 percent in the ≥60 years age group [71].

It is also important to note that children presenting with acute or chronic respiratory symptoms should be evaluated for more common conditions, such as asthma and acute chest syndrome, in addition to evaluation for PH. (See “Overview of the pulmonary complications of sickle cell disease” and “Acute chest syndrome (ACS) in sickle cell disease (adults and children)”.)

Given the often delayed appearance of symptoms and the increased morbidity and mortality associated with elevated pulmonary pressures by echocardiogram, we screen for PH, consistent with 2014 guidelines from the American Thoracic Society (ATS) [72,73]. This includes a one-time transthoracic Doppler echocardiogram in asymptomatic children with SCD between the ages of 8 and 18 years. Once individuals with SCD are 18 years old, Doppler echocardiography is used every one to three years. In contrast to the ATS guideline, an expert panel from the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH) found insufficient evidence to recommend screening for PH in asymptomatic individuals [6].

An elevated tricuspid regurgitant jet velocity on echocardiographic screening may not be only due to hemolysis; it may be a marker of risk for other conditions, including venous thromboembolic disease and disordered sleep breathing [73]. Details of the management of patients with abnormal findings from non-invasive screening, which may include additional screening, supplemental oxygen, diuretics, escalation of hydroxyurea therapy, anticoagulation, and/or pulmonary vasodilator therapy, are presented separately. (See “Pulmonary hypertension associated with sickle cell disease” and “Overview of the pulmonary complications of sickle cell disease”.)

Preconception counseling and screening for red blood cell alloantibodies is provided to individuals of childbearing age who are planning a pregnancy [6,23]. Referral of a partner of unknown SCD status for hemoglobinopathy screening is appropriate prior to conception. (See “Sickle cell disease: Obstetric considerations”.)

Osteopenia and osteoporosis are common findings in patients with SCD. (See “Acute and chronic bone complications of sickle cell disease”, section on ‘Osteopenia and osteoporosis’.)

However, there is a lack of evidence of an association of screening abnormal bone density and clinical symptoms; therefore, bone density testing is individualized and may follow standard recommendations. We perform bone density testing at 12 years of age and every one to three years thereafter, acknowledging lack of supporting evidence. (See “Osteoporotic fracture risk assessment”, section on ‘Medical diseases’ and “Evaluation and treatment of premenopausal osteoporosis”, section on ‘Screening’.)

In SCD patients who are symptomatic with osteoporosis, bisphosphonate therapy is beneficial in stabilizing bone loss [76,77]. (See “Bisphosphonate therapy for the treatment of osteoporosis”.)

Growth disturbances are common in SCD and have multiple etiologies that can be corrected. Correction of nutritional deficiencies may be beneficial, particularly zinc, which is associated with improved linear growth and weight gain [79]. (See ‘Nutrition’ above.)

An increased metabolic rate resulting in elevated resting energy expenditure and increased caloric requirements is common and may be improved by caloric intake or decreasing energy expenditures [80-82]. Transfusion therapy or hydroxyurea decreases metabolic rate and improves growth.

Monitoring growth and weight velocity may uncover growth hormone disturbances, which are responsive to growth hormone replacement [83]. Generally, we watch closely before initiating a more extensive evaluation because of the known rate delayed maturation.

  • End-organ dysfunction– Routine evaluations and treatments should be tailored for individual patients when co-morbidities are present (eg, chronic kidney disease, interstitial lung disease). This is especially true for adults with SCD, as end-organ dysfunction is prevalent.

OUTPATIENT MANAGEMENT OF SPECIFIC CONDITIONS

Mental health — Depression is underdiagnosed in adolescents and adults with SCD. In adults with SCD, depression (defined as a patient health questionnaire [PHQ]-9 score of ≥10 on two separate occasions at least four weeks apart) occurred in 16 percent, and depression was an independent risk factor for earlier mortality after adjustment for heart, lung, and kidney disease [84].

Racism-based discrimination in healthcare is associated with depression, sleep disturbance, and increased disease severity. In adults with SCD, discrimination correlated with greater clinical pain severity and enhanced sensitivity to multiple laboratory-induced pain measures, in addition to depression and sleep disturbances [85]. Patient perception of discrimination correlates with reduced trust and decreased adherence to treatment recommendations [86]; the establishment of trust is likely to improve patient overall outcomes. (See “Use of race and ethnicity in medicine”, section on ‘Effects of racism’ and “Acute vaso-occlusive pain management in sickle cell disease”, section on ‘Provider misperceptions that interfere with the assessment’.)

At least annual screening for depression and annual screening for neurocognitive deficits that may impair decision making and complex problem solving should be considered, often using a PHQ-9 tool. (See “Screening for depression in adults”, section on ‘Patient Health Questionnaire-9’.)

Therapy for depression should be addressed when appropriate. (See “Overview of prevention and treatment for pediatric depression” and “Major depressive disorder in adults: Approach to initial management”.)

Leg ulcers — The clinical characteristics and natural history of skin ulcers in individuals with SCD differ from those seen in individuals with other hemolytic anemias. Severe pain at the wound site is disproportionately greater in SCD than in other populations. Animal models support this observation.

We do not routinely evaluate for peripheral vascular disease with ankle brachial pressure index or for osteomyelitis, unless there is clinical suspicion.

Although many systemic and local therapies have been examined, the mainstays of therapy are wound care, compression, bedrest, and SCD-based therapy with hydroxyurea or chronic transfusions. When necessary, consultation with specialty programs that treat chronic extremity ulcers may be beneficial. Components of management may include the following [88-92]:

  • Pain control– Pain control should be provided without delay. Systemic opioids are often used. Topical opioids also have been found to relieve pain, decrease local fluid extravasation, and facilitate healing [93,94].
  • Edema– Local edema must be minimized with rest, lower extremity elevation, and compression bandages. In some cases, diuresis is also appropriate. Coban compression may be more beneficial than Unna boots.

Bedrest is essential for healing of large and/or recalcitrant ulcers, although adherence is challenging [95,96].

  • Debridement and grafting– Therapeutic debridement is important to remove fibrotic tissue and stimulate healing. In general, we initially refer the patient to a wound care specialist for debridement, dressing changes and, if necessary, topical antibiotics [97]. Wet to dry dressings and Duoderm hydrocolloid dressings may also facilitate healing.

Grafts may be necessary, but they have a very high failure rate and should be used conservatively [98].

  • Antibiotics – Infections require treatment, but antibiotics are often not helpful and should be used appropriately.
  • Nutrition – Many patients with SCD and skin ulcers have multiple other problems that impair wound healing, including malnutrition, vitamin D and nutritional deficiencies. (See ‘Nutrition’above.)
  • Mental health– Depression and other mental health disorders also need to be addressed as these impact wound care. (See ‘Mental health’above.)
  • Transfusions or hydroxyurea– In our experience, repeated transfusion therapy accelerates wound healing and is often a core therapy [99]. Hydroxyureamay be beneficial if not currently being taken, even though hydroxyurea-related skin ulcers have been reported. Patients can be managed initially with hydroxyurea and transitioned to chronic transfusion, or treated with chronic transfusion initially, depending on other comorbidities and patient factors.

Multiple therapies that may be beneficial remain unproven, including Apligraf (a skin equivalent), topical sodium nitrite 2% cream, RGD peptide dressings, and topical Timolol [100-103]. We do not routinely use these therapies.

Anemia — SCD causes chronic compensated hemolytic anemia with increased reticulocyte count. Beyond this, patients can develop worsening anemia due to other causes related to or unrelated to SCD. (See “Overview of the clinical manifestations of sickle cell disease”, section on ‘Anemia’.)

Pain management — Acute vaso-occlusive pain episodes are one of the most frequent reasons for individuals with SCD to seek medical attention. Chronic pain is a significant problem; by adulthood, one-half of individuals with SCD have chronic pain [104].

Development of a pain plan and management of acute pain episodes, chronic pain, preventive strategies, and opioid side effects are discussed in detail separately. (See “Evaluation of acute pain in sickle cell disease” and “Acute vaso-occlusive pain management in sickle cell disease”.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See “Society guideline links: Sickle cell disease and thalassemias” and “Society guideline links: COVID-19 – Index of guideline topics”.)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

PATIENT PERSPECTIVE TOPIC

Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See “Patient perspective: Sickle cell disease”.)

SUMMARY AND RECOMMENDATIONS

 

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