Pediatric Annals

Special Issue Article 

Sickle Cell Disease: A Primer for Primary Care Providers

Sabrina Kimrey, MD; Kay L. Saving, MD

Abstract

Sickle cell disease is an autosomal recessive disorder with significant global impact. This disorder causes the production of a dysfunctional hemoglobin, which leads to sickling of erythrocytes and ultimately hemolysis, endothelial dysfunction, vaso-occlusion, and sterile inflammation. These cellular level processes produce end-organ changes that ultimately result in specific risks and preventive care needs, unique emergency situations, and long-term complications for patients. Options for the treatment of sickle cell disease are increasing. Thus far, hydroxyurea is the most proven treatment and has been shown to reduce vaso-occlusive crises in children and adults and preserve organ function. Other therapies, both disease modifying and curative, are emerging and will hopefully have a substantial effect in the near future. [Pediatr Ann. 2020;49(1):e43–e49.]

Abstract

Sickle cell disease is an autosomal recessive disorder with significant global impact. This disorder causes the production of a dysfunctional hemoglobin, which leads to sickling of erythrocytes and ultimately hemolysis, endothelial dysfunction, vaso-occlusion, and sterile inflammation. These cellular level processes produce end-organ changes that ultimately result in specific risks and preventive care needs, unique emergency situations, and long-term complications for patients. Options for the treatment of sickle cell disease are increasing. Thus far, hydroxyurea is the most proven treatment and has been shown to reduce vaso-occlusive crises in children and adults and preserve organ function. Other therapies, both disease modifying and curative, are emerging and will hopefully have a substantial effect in the near future. [Pediatr Ann. 2020;49(1):e43–e49.]

Sickle cell disease (SCD), an autosomal recessive hemoglobinopathy, affects approximately 100,000 people in the United States and millions worldwide.1 It occurs in approximately 1 in 365 African-American births and 1 in 16,300 Hispanic-American births; in the US, SCD affects racial/ethnic minorities almost exclusively.1 Worldwide, SCD is most common in people with ancestry from sub-Saharan Africa, Central America, northern South America, Brazil, Saudi Arabia, India, and Mediterranean countries such as Greece, Italy, and Turkey.1

SCD causes significant economic impact, both on a personal and a national level. For example, one study found that in 2005 medical expenditures for children with SCD averaged $11,702 for children with Medicaid and $14,722 for children with employer-sponsored insurance.2 Another study found that from 1989 to 1993 a yearly average of 75,000 US hospitalizations due to SCD occurred, costing approximately $475 million annually.1 Despite the significant human and economic impact of SCD, hematologists specializing in SCD are scarce, making it necessary for primary care providers to have knowledge of this disease.

Sickle hemoglobin (HbS) results from a single-point missense mutation in the beta-globin gene of chromo-some 11, which substitutes valine for glutamate, resulting in a hemoglobin that polymerizes when deoxygenated.3 The polymerized proteins form stiff rods, causing the erythrocytes to adopt a “sickle” shape. These sickled erythrocytes, unlike healthy red blood cells, are vulnerable to hemolysis, leading to chronic anemia. Rigidity also prevents them from deforming to flow smoothly through capillaries, causing occlusion and subsequent oxygen deprivation in the downstream tissues. All of the manifestations of SCD, both acute and chronic, ultimately result from cellular level pathophysiology—hemolysis leading to endothelial dysfunction, sickling leading to vaso-occlusion, and both endothelial dysfunction and vaso-occlusion leading to sterile inflammation.4

SCD is part of standard newborn screening in every US state. Results compatible with a SCD hemoglobin genotype (mainly hemoglobin SS [HgbSS], hemoglobin S-beta thalassemia plus [Hgb SB+], hemoglobin S-beta thalassemia zero (HgbSB0), hemoglobin SC [Hgb SC], hemoglobin SD, hemoglobin SE) should initiate timely pediatric hematology referral. The HgbSS and HgbSB0 genotypes are generally the most clinically severe, although there is great phenotypic variability within each genotype.5 Even parents of newborns with screening tests indicative of sickle cell trait benefit from education on the rare but significant health risks of S trait, as well as genetic implications for future pregnancies.

Primary Care

Risk of Invasive Pneumococcal and Meningococcal Disease

There are several areas concerning the primary care of patients with SCD that are unique, all of them a direct result of the disease's pathophysiology. Because of repeated vaso-occlusive events, nearly all patients with SCD infarct their spleen at some point; those with HgbSS disease usually by age 1 year, and those with HgbSC or HgbSB+ and HgbSB0 approximately during adolescence. Because functional asplenia6 increases these patients' risk of bacteremia/sepsis, particularly from encapsulated bacteria, initiation of penicillin prophylaxis (eg, 125 mg orally 2 times per day until age 3 years, then 250 mg 2 times per day until age 3–5 years)7 is vital. Despite this long-standing recommendation, a 2018 study in Pediatrics found that only 18% of patients received adequate prophylaxis, and that “each additional SCD related outpatient visit and well-child visit was associated with incrementally increasing odds of receiving >300 days/year of antibiotic.”8 This highlights the importance of evaluating antibiotic compliance at every visit and carefully exploring barriers to adherence; it also implies that monitoring antibiotic adherence, even at visits not primarily focused on SCD, and following up promptly and persistently to reschedule missed visits might also be beneficial. In addition, providers should prioritize standard pneumococcal and Haemophilus influenzae type b vaccines in patients who are behind schedule and ensure the 23-valent pneumococcal and meningococcal A and B vaccines are administered at the appropriate ages specific to patients with SCD.9,10

Pre-Anesthesia Care

Because of the risk of severe anesthetic and/or perioperative complications, preprocedural clearance requires special consideration in the SCD population. For patients undergoing anesthetized minor procedures such as dental work, typanostomy tubes, or tonsil-lectomy/adenoidectomy,11 the recommendation is still that, at minimum, they receive adequate intravenous (IV) hydration prior to the procedure, and that some patients receive simple or partial exchange transfusion to bring the hemoglobin level to ≥10 g/dL, given the balance of risk and benefit.7 For higher-risk procedures such as abdominal surgery in patients with SCD, preoperative transfusion is associated with a decreased risk of postoperative complications such as vaso-occlusive crises, stroke, or acute chest syndrome (ACS).12,13

Contraception and Prepregnancy Counseling

Contraception and prepregnancy counseling of teens and young adults in the primary care practice have special caveats in patients with SCD. Any patient with SCD or sickle cell trait should be counseled on the risk of passing the abnormal gene to offspring, and encouraged to discuss partner testing, if unknown. For women who are not currently desiring pregnancy, the SCD criteria regarding contraceptive use14 cite either no restrictions or that advantages generally outweigh risks for all forms of contraception listed. Although SCD itself is not an absolute contraindication to estrogen-containing forms of contraception, certain complications of SCD like stroke are absolute contraindications, so progestin-only formulations are always preferred due to thrombotic risk.

Because pregnant women with SCD are more likely to experience preeclampsia, venous thromboembolism, and maternal mortality than those without SCD,7 they should be counseled about these risks prior to pregnancy and promptly referred to a maternal-fetal medicine specialist once pregnant. Their infants are more likely to be born early and are at increased risk of hemolytic disease of the newborn if the mother had previously received a transfusion.

Screening/Referral to Subspecialty Care

Repeated vaso-occlusive events, endothelial damage, and hemolysis inevitably lead to chronic end-organ damage, some of which may manifest in childhood. Most critically this includes a risk of stroke. Hemoglobin SS patients should have annual transcranial Doppler (TCD) beginning at age 2 years (or when the patient can comply with examination) until age 16 years.7 Initiation of a chronic transfusion program15 with a possible switch to hydroxyurea later5,16 has proven to be an effective primary stroke prevention strategy in patients with elevated TCD velocities. Even in patients without stroke or elevated TCD velocities, microinfarcts as well as cortical thinning due to chronic hypoxemia still occur and over time lead to cognitive dysfunction. These issues are often compounded by adverse childhood experiences and toxic stress associated with poverty or caregiver physical or mental illness, making close monitoring of developmental milestone acquisition and behavioral issues crucial in children with SCD. Using early intervention services for toddlers and later neuropsychological testing, individualized educational plans, 504 plans, and other appropriate psychosocial support services for school-age children and adolescents can mitigate this dysfunction, but it can remain a significant challenge.17

Although the chronic cardiothoracic complications, such as pulmonary hypertension, rarely present in childhood, a fair number of pediatric patients with SCD have comorbid respiratory conditions such as asthma and obstructive sleep apnea (OSA). A 2014 study found a higher prevalence of OSA (41%) in SCD patients than in the general population.18 A prospective study of 1,963 people with SCD from birth through adulthood found that those with asthma had more than a 2-fold higher risk of mortality after adjusting for established risk factors.19 Both asthma and OSA exacerbate tissue oxygen deprivation and increase the risk for ACS, a leading cause of hospitalization and death.5 Good asthma control and prompt referral to a pediatric pulmonologist for respiratory conditions have great utility in protecting patients with SCD from acute and chronic respiratory complications.

Although more rare in young children, in adolescence the long-term complications associated with chronic hemolysis, chronic tissue oxygen deprivation, and endothelial damage begin to manifest. These include kidney disease (which can be exacerbated by chronic nonsteroidal anti-inflammatory drugs [NSAIDs] use for pain), hypertension (systemic and pulmonary), retinopathy, hepatobiliary disease (acute cholescystitis, cholelithiasis), and avascular necrosis. These conditions can be screened for by measures such as urine microalbumin, regular blood pressure measurement, and a thorough systems review at visits, with further testing and subspecialty referral for any abnormalities found. See Table 1 for more detailed recommendations.

Health Maintenance and Screening Recommendations for Sickle Cell Disease

Table 1.

Health Maintenance and Screening Recommendations for Sickle Cell Disease

Emergency Care

Even with adequate access to primary care, which many people do not have, patients with SCD use emergency department (ED) services often; the most common reason being pain due to acute vaso-occlusive crises (VOC). Every patient with SCD should have a pain plan that includes conservative measures (increased oral fluids, oral nonopioid pain medications, heating pad/warm bath) to begin at home at the onset of pain crises; as well as additional recommendations (including appropriate opioid doses) for ED providers not familiar with the patient. In light of the current opioid epidemic and resultant hesitancy to prescribe them for VOC pain, a pain plan can be an effective, structured way to balance appropriate care for patients with prescriber comfort.20 General ED principles of VOC management include starting analgesic therapy within 30 minutes of triage or 60 minutes of registration. Acetaminophen administration, if not already used by the patient at home, is appropriate, but rarely adequate. For mild to moderate pain, oral or parenteral NSAIDs should be employed in the absence of a contraindication such as kidney disease, but these too may be insufficient. In children and adults experiencing a VOC with severe pain, rapid initiation of parenteral opioids is the recommended therapy.7

Because of the functional asplenia and increased risk of invasive pneumococcal disease previously discussed, fever in a young patient with SCD is a medical emergency. Providers should define fever for families and provide an appropriate thermometer if the household is lacking one. Any report of fever to office or ED triage staff should result in prompt physical examination, evaluation of a complete blood count with differential, reticulocyte count, and blood culture, and urine sample for culture if indicated by symptoms. This should be followed by rapid administration of IV antibiotics with broad empiric coverage, typically 50 mg/kg of ceftriaxone.7

Respiratory disease, another common cause for ED presentation in patients with SCD, can rapidly progress to serious illness. Any patient presenting with lower respiratory symptoms such as cough, wheezing, tachypnea, retractions, or shortness of breath should have pulse oximetry and a chest X-ray (CXR) performed, even if afebrile or clinically appearing to more likely have viral disease.7 The presence of any of the above symptoms in conjunction with a new infiltrate on CXR constitutes ACS. Even if a new infiltrate is not yet evident, CXR findings often lag behind clinical presentation and patients should be hospitalized and monitored for the development of ACS. Preferably, this should be at a facility with exchange transfusion capability and pediatric intensive care unit services, under the care of a provider with experience in ACS management. ACS is the principal cause of mortality in pediatric patients with SCD and rapid deterioration is not uncommon.7

Children with SCD are also at risk for life-threatening acute anemia, due to a severe hemolytic crisis, an aplastic crisis (often associated with parvovirus infection), or splenic sequestration. All of these conditions require thoughtful transfusion support until resolution of the underlying insult. Blood that is sickle negative, cytomegalovirus safe, and phenotypically matched (on the most common antigens that cause alloimmunization—Cc, Ee, and Kell—at minimum) is preferred.7 The prompt delivery of increased oxygen-carrying capacity in the form of packed red blood cells (PRBC) must be balanced with the risk of cardiac overload from too rapid a transfusion. With severe anemia, using multiple 5 mL/kg PRBC aliquots, each transfused over 4 hours, allows transfusion to a safe, although not necessarily baseline, level.7

Patients with SCD presenting with symptoms consistent with stroke should be emergently evaluated with physical examination and immediate computed tomography scan. If stroke is confirmed, care should proceed as it would for any patient with stroke with the key addition of an immediate exchange transfusion in consultation with a sickle cell specialist.

Priapism, a vaso-occlusive event in the penile vasculature of male patients with SCD, can result in permanent injury if not addressed quickly. It is important to educate patients and parents about this condition and the risk of permanent injury during regular health maintenance visits. Young patients are often reticent to mention to their parents or health care providers that they are having symptoms of priapism, so it is essential that providers take the initiative to discuss it. If priapism occurs, initiate home interventions including increased oral hydration, attempt to urinate, oral pain medication, and a warm bath. If after 2 hours priapism persists, ED care is needed for IV fluids and pain medications, possible transfusion, and urology consultation in resistant cases. See Figure 1 for more examples of sickle cell complications.

Acute and chronic complications of sickle cell disease. Reprinted with permission from Kato and Gladwin.31

Figure 1.

Acute and chronic complications of sickle cell disease. Reprinted with permission from Kato and Gladwin.31

Therapies: Current and Emerging

Hydroxyurea (HU), gained US Food and Drug Administration (FDA) approval for adults with HgbSS and and HgbSB0 thalassemia SCD in 1998 after the 1995 publication of a landmark study showing its ability to reduce painful vaso-occlusive episodes.21 Completion of pediatric trials resulted in the 2002 National Heart, Lung, and Blood Institute guideline22 recommendations for pediatrics with specific indications, such as frequent vaso-occlusive episodes or history of ACS. Guideline revisions in 20147 recommended all children with SS or HgbSS and HgbSB0 thalassemia SCD be offered HU, starting at age 9 months. Hydroxyurea primarily acts through induction of fetal hemoglobin production, but also helps prevent vaso-occlusion by inhibiting adhesion between white cells, platelets, endothelial cells, and red blood cells; as well as decreasing endothelial dysfunction from ongoing hemolysis (Figure 2).23 The once daily initial 20 mg/kg/dose is gradually increased over several months to the maximal tolerated dose, which is up to 35 mg/kg/dose. Pediatric trials have shown reduced pain, dactylitis, transfusions, hospital admissions, and length of stay, as well as preservation of organ function if started at a young age. All large clinical trials have been in patients with HgbSS or HgbSB0, but it has been used effectively in other types of SCD when specific clinical indications existed.

The molecular pathophysiology of sickle cell disease. Reprinted with permision from Sundd et al.23

Figure 2.

The molecular pathophysiology of sickle cell disease. Reprinted with permision from Sundd et al.23

The FDA approved L-glutamine in 2018 for patients older than age 5 years after clinical trials showed a significant decrease in the incidence of VOC and hospital days in patients taking the powder orally twice daily;24 this was independent of HU use, raising the possibility of an additive effect. It is thought to reduce the oxidative stress of SCD red blood cells, reducing vaso-occlusion and pain. Patients should take the specific pharmaceutical grade preparation used in the trial and not unregulated products sold in health food stores.

Recent interest in SCD-modifying treatments has increased as the underlying complex pathophysiology becomes better understood, the recognition of HU success expands, and the critical importance of easily distributed oral medication is demonstrated in places outside the US, such as Africa, where the burden of SCD is heavily manifested.25 These investigative drugs either target HbS polymerization and sickling, or the downstream pathophysiologic sequelae seen in the inflammatory vasculopathy and oxidative stress of SCD.25–27

One monthly IV drug, humanized anti-P-selectin monoclonal antibody crizanlizumab, prevents cell-to-cell adhesion of sickled red blood cells, endothelium, leukocytes, and activated platelets by blocking the cell adherence molecule, P-selectin, expressed by these cells during vaso-occlusion.28 Voxelotor (GBT440-001), a once-daily oral HbS polymerization inhibitor, increases hemoglobin's affinity for oxygen, blocking red blood cell sickling, resulting in higher hemoglobin levels and reduced markers of hemolysis.29 These are two examples of a number of SCD-modifying drugs currently in clinical development or trial.

The only current cure for SCD is hematopoietic stem cell transplantation, which has an 90% success rate when a matched sibling is used for the donor.4 The barriers of donor availability and significant associated toxicities (ie, infection, death, graft-versus-host disease, infertility) are substantial, with only 10% to 20% of patients with SCD having an acceptable donor.4 Transplants with haploidentical donors, cord blood, and matched unrelated donors have also been used, but increased graft rejection and complications restrict these methods to use only within a clinical trial.4

Recent initial successes in gene therapy have used lentiviral or other vectors to insert a beta globin gene, which is modified to inhibit hemoglobin S polymerization, into hematopoietic stem cells harvested from the patient's bone marrow. These stem cells are then reinfused into the patient, become engrafted, and begin producing the modified beta globin proteins. This method offers eventual widespread cure with less toxicity than full hematopoietic stem cell transplantation.30 Additional methodologies under investigation involve lentiviral vectors encoding for Hemoglobin A and CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) technology.4

Conclusion

Despite how long we have understood the fundamental pathophysiology of SCD, the average lifespan of SCD patients in the US is less than 50 years. We, as caregivers to the youngest of these, can intervene early in their lives, having an enormous positive impact on their futures. In light of the many promising advances on the horizon, such as disease-modifying treatments currently under study, prospects for cure with new genetic approaches, creation of national registries and a Sickle Cell Disease Clinical Trials Network to foster collaborations in research, access to care, and medical/patient partnerships, many feel there is a strong future for positive change. We must all work to continue this momentum.

References

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Health Maintenance and Screening Recommendations for Sickle Cell Disease

Screening/Preventive Measures Timing/Frequency
Medications
Oral penicillin (or other appropriate pneumococcal prophylaxis if penicillin allergic) Daily starting at diagnosis and continuing until at least age 5 years
Hydroxyurea Daily starting at age 9 months and continuing indefinitely for patients with HgbSS and S-beta genotypes
Folic acid supplementation Consider starting at age 9 months or when taking foods well
Iron supplementation Consider from age 6–12 months in children at increased risk of iron deficiency
Procedures
Transcranial Doppler Starting at age 2 years or when able to be compliant with examination; continue yearly until age 16 years if normal; if >170 cm/s, refer to specialist promptly
Dilated eye examination Every 1–2 years beginning at age 8–10 years
Pulmonary function tests Baseline and as needed in patients who are symptomatic and old enough to comply with examination; not recommended in people who are asymptomatic
Immunizations According to standard CDC childhood schedule plus 23-valent pneumococcal vaccine, meningococcus A vaccine, and meningococcus B vaccine according to schedule for functional asplenia
Measurement of blood pressure According to NHLBI guidelines
Laboratory testing
Red blood cell phenotyping Once any time after age 6 months
Complete blood count, reticulocyte count Prior to initiating hydroxyurea; monthly while titrating hydroxyurea to maximum tolerated dose; every 2–3 months while on a stable dose of hydroxyurea; at baseline and every 6 months if not on hydroxyurea
Hemoglobin electrophoresis At diagnosis; every 3 months while on hydroxyurea; prior to major surgical procedures requiring anesthesia
Ferritin Every 4 months for patients receiving chronic transfusion
Complete metabolic panel Yearly in patients receiving chronic transfusion; consider yearly in all patients
Urinalysis Yearly beginning at least by age 10 years; consider at younger ages
Urine albumin-creatinine ratio (first morning void) If urinalysis positive for proteinuria, refer to specialist
Education
Transition to adult care Discuss transition process; provide appropriate education; and encourage patient engagement/ownership of care at least yearly starting at age 12 years
Individualized educational plan/504 plan Re-evaluate needs at least yearly starting when patient begins formal education (pre-K or kindergarten)
Authors

Sabrina Kimrey, MD, is an Assistant Professor of Pediatrics, Division of Pediatric Hematology/Oncology, University of Illinois College of Medicine Peoria; and a Practicing Clinician, St. Jude Midwest Affiliate. Kay L. Saving, MD, is the Associate Head, Department of Pediatrics, and a Professor and the Division Head, Division of Pediatric Hematology/Oncology, University of Illinois College of Medicine Peoria; the Medical Director, OSF Healthcare Children's Hospital of Illinois; and the Medical Director, St. Jude Midwest Affiliate.

Address correspondence to Sabrina Kimrey, MD, University of Illinois College of Medicine Peoria, 530 N.E. Glen Oak Avenue, Peoria, IL 61637; email: skimrey@uic.edu.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20191210-01

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