Author(s): Sunil K Jain, MD Madison Metheny, Paul Varghese, MD, Austin Miller, DO
Originally published: June 14, 2023 Last updated: May 14, 2026
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Disease/Disorder

Definition

Sickle Cell Disease (SCD) is a group of inherited red blood cell disorder that affects hemoglobin and results in the characteristic “sickling” of red blood cells that is responsible for hemolytic anemia, pain crises, and multiorgan dysfunction.1

Etiology

SCD is inherited in an autosomal recessive manner. The most common form of SCD occurs when there is a point mutation in both copies of a patient’s HBB gene on chromosome 11, resulting in a replacement of both beta-globin subunits of hemoglobin with hemoglobin S (HbS).2,3 Phenotypic expression will vary depending on the type of mutation (HbS, HbD, HbE, or HbO) and number of copies of mutated genes (sickle cell trait vs sickle cell disease).4

Epidemiology including risk factors

Sickle cell disease is one of the most common inherited red blood cell disorders in the world. SCD affects millions worldwide with an estimated 300,000 people born with it every year. It occurs most commonly in Sub-Saharan Africa regions where malaria is most prevalent, due to the protective effect of the sickle cell allele against malaria.5-7  Risk factors that relate to increased inheritance of SCD include family history and people of African descent. Per the CDC, approximately 100,000 people in the United Sates are living with SCD, including 1 in 365 African Americans and 1 in 16,300 Hispanic Americans that are born with the disease.3,7  

Patho-anatomy/physiology  

SCD results from a point mutation in the HBB gene where valine replaces glutamic acid. This creates deoxygenated hemoglobin S (HbS) which polymerizes into rigid fibers, causing the characteristic sickling of red blood cells. These cells lead to vaso-occlusion, tissue ischemia, and the hallmark hemolytic anemia and painful crises seen in the pediatric population.8  The cumulative effect of these repeated ischemic events necessitates a comprehensive rehabilitation approach to address the resulting functional impairments and chronic pain.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

As mentioned above, SCD is not a single disorder, but rather a group of inherited red blood cell disorders with varying clinical severity. SCD Type HbSS is the most common form and the most severe, but other common types can include HbSC, and HbS beta thalassemia. 1 It is usually detected at birth during newborn screening and symptoms generally will not arise until around 6 months of age because of the protective effects of fetal hemoglobin. Symptoms can include vaso-occlusive crises, acute chest syndrome, splenic sequestration, dactylitis, and priapism.9 SCD can also increase the risk of stroke and developmental delays. Life expectancy has steadily increased from 28 in 1979 to 43 in 2014 due to improvements in symptom management and patient education.7,10 Common causes of death in the pediatric population are infection, acute chest syndrome, acute splenic sequestration, and stroke.

Specific secondary or associated conditions and complications

Severity of symptoms and complications vary depending on the type of SCD. Conditions and complications not mentioned above can include avascular necrosis, pulmonary hypertension, leg ulcers, vision loss, and sleep apnea.5

Essentials of Assessment

Assessment must extend beyond physical symptoms to include Health-Related Quality of Life (HRQOL) metrics. SCD is a multisystem disease that affects the physical, psychological, and social aspects of patients’ lives, leading to lower HRQOL compared to the general population.11 Identifying barriers to treatment adherence, such as the psychosocial impact of frequent hospitalizations, is a critical component of the physiatric evaluation to ensure successful community and school reintegration.

History

Sickle cell is often diagnosed via genetic testing at birth due to mandatory SCD screening for newborns in all 50 states since 2008. However, symptoms will not present themselves until around 4-6 months. Sickle cell should be suspected if the patient or family mentions unexplained painful episodes suggestive of vaso-occlusive crises.5 Age of onset and symptoms will be key in identifying the type of SCD.

Physical examination

Physical examination for infants and children suspected of SCD should focus on musculoskeletal, abdominal, HEENT, and skin findings.  Severe inflammation of the finger and toe joints on musculoskeletal examination may suggest dactylitis. Abdominal findings may include splenomegaly. Skin and HEENT exam may show jaundice. A complete multisystem physical exam is important to assessing all potential complications.9 Physical examination should specifically screen for impairments in balance and lower extremity muscle strength. Evidence indicates that children and adolescents with SCD exhibit significantly lower scores on balance subtests and reduced knee extensor and flexor strength compared to healthy peers, which directly impacts functional mobility.12

Functional assessment

Functional assessments are a key component when evaluating SCD patients. Functional impairment due to severe pain from vaso-occlusive crises or underlying neurological issues will vary among different types of SCD.13

Objective measurement of functional capacity is vital for longitudinal tracking. Physiatrists should utilize standardized tools such as the 6-Minute Walk Test (6MWT) to assess cardiopulmonary endurance and exercise tolerance, which are often limited in children with SCD due to chronic anemia and pulmonary complications. Furthermore, the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) should be employed to provide a comprehensive assessment of a child’s abilities in daily activities, mobility, and social-cognitive function.12These tools allow the clinical team to quantify functional morbidity and tailor specific rehabilitative interventions.

Laboratory studies

Diagnosis of SCD is vital in order to begin prophylactic treatment as soon as possible. Following the initial newborn screening, an additional blood test is required to confirm the initial findings.  While there is no gold standard test, a combination of screening tests such as CBCs, peripheral blood smears, and sickling tests are routinely done along with confirmatory tests such as hemoglobin electrophoresis.14 Furthermore, CBCs and reticulocyte count should be performed at every visit to establish a baseline value.

Imaging

Imaging is not used in the diagnosis of SCD but can be used for the management of the disease. Transcranial Doppler or MRI is commonly used to screen patients at high risk of stroke.7 Other forms of imaging for gastrointestinal, respiratory, and musculoskeletal symptoms may be appropriate depending on patient presentation.  

Supplementary assessment tools

A child’s cognitive abilities must be assessed at every visit, and a drastic change in performance may suggest a “silent cerebral infarct” that warrants immediate investigation.7 Psychiatric assessment is suggested to identify possible depression.1

Early predications of outcomes

Early predictions of outcomes depend on the type of SCD. Although life expectancy has increased in the last few decades due to new treatment options, it is still shortened by more than 2 decades compared with the general population.7 The primary cause of death among patients with SCD in the United States has also shifted. A few decades ago, the primary cause was acute cardiac complications and infection whereas recent studies have shown that the current leading cause of death is chronic cardiac complications.7,15

Environmental

Environmental factors such as cold temperatures, dehydration, insufficient rest, and stress can trigger pain-crisis and should be avoided.1  

Social role and social support system

Studies have shown that complications from SCD can take a large emotional toll on a child, and approximately 25% of all SCD patients suffer from depression.1 As a child ages and begins to understand his disease, social workers, psychologists, and child life specialists may be necessary to assist the child in adjusting to school and personal life.16 Patient and family support is crucial as well and there are also numerous community support groups in many states that families may benefit from.

Professional issues

Accommodations may be necessary for SCD patients depending on the severity of symptoms. Patients with SCD have an increased risk of cognitive impairment thought to be due to silent cerebral infarcts and may require special arrangements at school.7 On average, patients usually have 3-4 vaso-occlusive crises a year, thus further necessitating the need for school and workplace accommodations.17

Rehabilitation Management and Treatment

Available or current treatment guidelines

Current treatment involves a mix of symptom management, transfusion, and medications for preventative measures. These include hypertransfusion which is a regimen of chronic blood transfusions designed to reduce sickle hemoglobin levels and reduce the risk of sickle cell disease complications such as stroke.18,19 Hydroxyurea is the primary medication used in the treatment of SCD. It shifts production of adult hemoglobin towards fetal hemoglobin, which is not affected by the sickle mutation, thus reducing the incidence of vaso-occlusive crises.7 Additional treatments that have been approved in the last 5 years include L-glutamine and voxelotor, which function to reduce the incidence of vaso-occlusive crises. These medications are generally only given if hydroxyurea is not tolerated. Crizanlizumab, a previously approved treatment, was found in a phase 3 randomized controlled trial to have limited additional benefit over standard therapy.20 

Supportive care involving nutritional management and social optimization may also be a topic of therapy. A systematic review and meta-analysis of randomized controlled trials found that supplementation with fatty acids and L-arginine significantly improved pain intensity, reduced vaso-occlusive crises, and decreased inflammation in children and adolescents with sickle cell disease. Vitamin D3 supplementation may reduce respiratory complications and length of hospital stay, although further studies are needed to confirm these effects.21 Socially, in a feasibility trial in northern Nigeria, enrolling malnourished siblings alongside children with sickle cell anemia improved nutritional outcomes, suggesting that family-centered interventions may enhance treatment success in resource-limited settings.22

Rehabilitative pain management focuses on shifting the patient from passive to active coping strategies. While the evidence for specific psychological therapies is evolving, the goal remains to utilize these interventions to reduce pain intensity and improve overall functional status. This includes addressing psychological comorbidities, such as depression and anxiety, which frequently complicate the rehabilitative course in pediatric patients.1 Rehabilitation programs must account for increased energy expenditure during gait. Research shows that children with SCD have a higher oxygen cost during walking, which may contribute to early fatigue and decreased participation in physical activities (Marchese et al., 2022). Intervention strategies should include energy conservation techniques and progressive aerobic conditioning to improve mechanical efficiency.12

Psychological and behavioral interventions

Psychological interventions serve as a cornerstone of comprehensive rehabilitation to mitigate the functional impact of chronic pain. Evidence suggests that psychological therapies, specifically cognitive behavioral therapy, may be effective in helping individuals with sickle cell disease to cope with their pain.1 These interventions should focus on biofeedback, relaxation techniques, and cognitive restructuring to improve the patient’s ability to participate in activities of daily living (ADLs) and reduce the psychosocial burden of the disease.

Coordination of care

Care of this complex condition requires an interdisciplinary approach that includes the following23

  • Primary physician
  • Physiatrist
  • Hematologist
  • Pediatrician
  • Geneticist
  • Neurologist
  • Cardiologist
  • Nephrologist
  • Pulmonologist
  • Social worker
  • Psychologist
  • Clinical care coordinator

Patient and family education

Families should be educated about acute and chronic symptoms of SCD in order to bring them to medical attention if necessary. Caregivers must be educated and trained in the following

  • Risk of splenic sequestration and daily palpation of the spleen
  • Patient requires urgent medical attention if a fever is present, even if the fever has resolved without the use of antipyretics24
  • Ability to recognize pain crisis and treat appropriately24
  • Ability to recognize acute chest syndrome and to seek appropriate care
  • Stroke risk and warning signs of a stroke
  • Priapism and when to seek assistance

If family or caretakers are unable to provide the level of support a SCD patient needs, then a referral to social service is recommended.

Both patient and family should also be given genetic counseling to make informed decisions in the future. Patients should be offered preconception counseling and their planned partner should be screened.3

Families and patients should be encouraged to learn more about SCD by visiting external sources.

Oftentimes, SCD patients experiencing a vaso-occlusive crisis are treated like drug seekers and do not receive the proper care. As adolescents transition to adulthood and begin to seek care on their own, they should be further encouraged to continuously educate themselves on their own condition and look into outreach projects and support groups so they can better advocate for themselves.25

Emerging/unique interventions

Current medications approved for SCD work by reducing the number of vaso-occlusive crises. Rivipansel is a molecule that was designed to bind all members of the selectin family involved in the adhesion of RBCs to vascular endothelium to shorten the duration of acute vaso-occlusive crises. It failed to meet its primary and secondary goals in Phase 3 testing in 2019 but was granted a rare pediatric disease designation in 2020 after post-hoc analysis showed some favorable results.7,26

Mitapivat, a first-in-class oral allosteric activator of pyruvate kinase, improves red blood cell survival by increasing ATP and decreasing 2,3-diphosphoglycerate, thereby reducing sickling. In the phase 2 portion of the global RISE UP randomized controlled trial, mitapivat demonstrated improvement in hemoglobin levels and markers of hemolysis in patients with sickle cell disease.27

Numerous gene therapy trials also continue to be explored.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

  • SCD is a lifelong disease that requires management via a multidisciplinary team.
  • Studies have shown that medication adherence is often difficult, so provider must be ready to offer alternatives.28
  • No lab or clinical findings can help a provider confirm pain, therefore patient-provider communication is crucial.
  • Likelihood of depression in SCD patients are correlated with pain severity.7
  • When taking a patient’s history, it is important for a physician to remain open-minded and unbiased to avoid instinctively characterizing a patient experiencing a vaso-occlusive crisis as a drug-seeker.
  • When treating patients in the ED, it is imperative that physicians remain mindful of deeply ingrained stigmatization of drug-seeking behavior and ensure that a SCD patient is provided with the treatment they need.

Cutting Edge/Emerging and Unique Concepts and Practice

Numerous gene therapy and gene technologies are currently being investigated in clinical trials. Rivipansel has shown promise as the first medication that can shorten the duration of an acute vaso-occlusive crisis.29 L-glutamine and voxelotor has shown promise in patients where hydroxyurea is not tolerated but requires further research to establish proper dosages for combination therapy.7 Exagamglogene autotemcel (exa-cel), a CRISPR/Cas9 gene-edited autologous hematopoietic stem cell therapy, eliminated vaso-occlusive crises in 97% of participants with severe sickle cell disease in the phase 3 CLIMB SCD-121 trial and was associated with clinically meaningful improvements in health-related quality of life.30 Gene-therapy efficacy may also vary depending on hematopoietic stem cell engraftment, and inflammatory alterations in the bone marrow environment may impair successful engraftment in some patients.31 For the physiatrist, these emerging therapies represent a potential shift from chronic symptom management to supporting patients through a ‘rehabilitative cure,’ focusing on long-term functional reintegration post-engraftment.

Gaps in the Evidence-Based Knowledge

  • Further research is needed to establish optimal combinations of medications if hydroxyurea is not tolerated
  • Continued research on Rivipansel is needed.
  • Only way to cure SCD is via stem cell transplant or gene therapy which requires more research
  • Voxelotor’s efficacy in patients under 4 years of age is unknown and needs further investigation.

References

  1. Anie KA, Green J. Psychological therapies for sickle cell disease and pain. Cochrane Database of Systematic Reviews. 2015;(5)
  2. Newby GA, Yen JS, Woodard KJ, et al. Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature. 2021;595(7866):295-302.
  3. Prevention CfDCa. Data & statistics on Sickle Cell Disease. 2022;
  4. Onimoe G, Rotz S. Sickle cell disease: A primary care update. Cleveland Clinic journal of medicine. 2020;87(1):19-27.
  5. Wastnedge E, Waters D, Patel S, et al. The global burden of sickle cell disease in children under five years of age: a systematic review and meta-analysis. Journal of global health. 2018;8(2):021103.
  6. Gardner K, Douiri A, Drasar E, et al. Survival in adults with sickle cell disease in a high-income setting. Blood, The Journal of the American Society of Hematology. 2016;128(10):1436-1438.
  7. Neumayr LD, Hoppe CC, Brown C. Sickle cell disease: current treatment and emerging therapies. Am J Manag Care. 2019;25(18 Suppl):S335-43.
  8. Sundd P, Gladwin MT, Novelli EM. Pathophysiology of sickle cell disease. Annual review of pathology: mechanisms of disease. 2019;14(1):263-292.
  9. Zúñiga P, Martínez C, González LM, et al. Enfermedad de células falciformes: Un diagnóstico para tener presente. Revista chilena de pediatría. 2018;89(4):525-529.
  10. Payne AB, Mehal JM, Chapman C, et al. Mortality trends and causes of death in persons with sickle cell disease in the United States, 1979-2014. Blood. 2017;130:865.
  11. Yang M, Elmuti L, Badawy SM. Health‐related quality of life and adherence to hydroxyurea and other disease‐modifying therapies among individuals with sickle cell disease: a systematic review. BioMed Research International. 2022;2022(1):2122056.
  12. Marchese V, Rock K, Harpold A, Salazar A, Williams M, Shipper AG. Physical impairment and function in children and adolescents with sickle cell disease: a systematic review. Archives of Physical Medicine and Rehabilitation. 2022;103(6):1144-1167. e2.
  13. Sil S, Goldstein-Leever A, Travers C, et al. Enhancing pain assessment in pediatric sickle cell disease by applying quality improvement science. Clinical practice in pediatric psychology. 2019;7(4):335-346.
  14. Arishi WA, Alhadrami HA, Zourob M. Techniques for the detection of sickle cell disease: a review. Micromachines. 2021;12(5):519.
  15. Desselas E, Thuret I, Kaguelidou F, et al. Mortality in children with sickle cell disease in mainland France from 2000 to 2015. Haematologica. 2020;105(9):e440.
  16. Wills KE, Nelson SC, Hennessy J, et al. Transition planning for youth with sickle cell disease: embedding neuropsychological assessment into comprehensive care. Pediatrics. 2010;126(Supplement_3):S151-S159.
  17. Stinson J, Naser B. Pain management in children with sickle cell disease. Pediatric Drugs. 2003;5(4):229-241.
  18. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. New England Journal of Medicine. 1998;339(1):5-11.
  19. Ware RE, Zimmerman SA, Sylvestre PB, et al. Prevention of secondary stroke and resolution of transfusional iron overload in children with sickle cell anemia using hydroxyurea and phlebotomy. The Journal of pediatrics. 2004;145(3):346-352.
  20. Abboud MR, Cançado RD, De Montalembert M, et al. Crizanlizumab with or without hydroxyurea in patients with sickle cell disease (STAND): primary analyses from a placebo-controlled, randomised, double-blind, phase 3 trial. The Lancet Haematology. 2025;12(4):e248-e257.
  21. Orsi BC, Gorski D, Krul NE, et al. The effects of nutritional supplementation for children and adolescents with sickle cell disease: A systematic review and meta-analyses. Clinical Nutrition. 2025;47:157-168.
  22. Murtala HA, Abdullahi SU, Gambo S, et al. Including malnourished siblings in treatment improves nutritional outcomes for children with sickle cell anemia in Northern Nigeria: Results from a feasibility trial. Nutrition Research. 2025;
  23. McAllister JW, Presler E, Cooley WC. Practice-based care coordination: a medical home essential. Pediatrics. 2007;120(3):e723-e733.
  24. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. Jama. 2014;312(10):1033-1048.
  25. McClish DK, Smith WR, Levenson JL, et al. Comorbidity, pain, utilization, and psychosocial outcomes in older versus younger sickle cell adults: the PiSCES project. BioMed research international. 2017;2017(1):4070547.
  26. Ali MA, Ahmad A, Chaudry H, et al. Efficacy and safety of recently approved drugs for sickle cell disease: a review of clinical trials. Experimental hematology. 2020;92:11-18. e1.
  27. Idowu M, Otieno L, Dumitriu B, et al. Safety and efficacy of mitapivat in sickle cell disease (RISE UP): results from the phase 2 portion of a global, double-blind, randomised, placebo-controlled trial. The Lancet Haematology. 2025;12(1):e35-e44.
  28. Heeney MM, Ware RE. Hydroxyurea for children with sickle cell disease. Hematology/oncology clinics of North America. 2010;24(1):199-214.
  29. Dampier CD, Telen MJ, Wun T, et al. Early initiation of treatment with rivipansel for acute vaso-occlusive crisis in sickle cell disease (SCD) achieves earlier discontinuation of IV opioids and shorter hospital stay: reset clinical trial analysis. Blood. 2020;136:18-19.
  30. Sharma A, Locatelli F, Bhatia M, et al. Improvements in health-related quality of life in patients with severe sickle cell disease after exagamglogene autotemcel. Blood Advances. 2025;9(24):6481-6490. 
  31. Sobrino S, Joseph L, Magrin E, et al. Severe inflammation and lineage skewing are associated with poor engraftment of engineered hematopoietic stem cells in patients with sickle cell disease. Nature Communications. 2025;16(1):3137.

Original Version of the Topic

Sunil K Jain, MD, James Kwok. Pediatric Sickle Cell Disease. 6/14/2023

Author Disclosure

Sunil K Jain, MD
Nothing to Disclose

Madison Metheny
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Paul Varghese, MD
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Austin Miller, DO
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