Sickle Cell Disease

Hemoglobin is formed when valine is substituted for glutamic acid at the sixth position of the beta-globin chain. This mutant hemoglobin polymerizes under stress (e.g., dehydration, cold environment, hypoxemia) and results in occlusion of blood flow and resultant complications that are the hallmark of sickle cell disease (SCD). Patients who have one sickle allele and one normal HbA allele are generally asymptomatic carriers (sickle cell trait, HbAS). In contrast, a number of genotypes constitute SCD, including homozygous hemoglobin SS (HbSS), hemoglobin S beta⁰-thalassemia (HbSβ⁰-thalassemia), hemoglobin S beta⁺-thalassemia (HbSβ⁺-thalassemia) and hemoglobin SC disease (HbSC).

In this section, we review the following:

• Common Complications of SCD

• Preventive Care and Treatment

• Additional Therapies for SCD

Complications of SCD

Although the clinical severity of SCD varies among genotypes, children with heterozygous SCD (HbSC etc.) in general tend to have complications later in life while those with homozygous SCD (HbSS) face complications as young children. In addition, co-inheritance of other globin gene variants (alpha-thalassemia, fetal hemoglobin expression) along with HbS modify the severity of disease complications. The information below is primarily derived from National Heart, Lung, and Blood Institute (NHLBI) evidence-based guidelines for management of patients with SCD.

Common complications of SCD include the following:

• vaso-occlusive crises

• acute chest syndrome

• fever

• splenic sequestration

Vaso-Occlusive Crisis

Vaso-occlusive crisis (VOC) is the most common complication of SCD and results from tissue ischemia (most often in bone and bone marrow) due to occlusion of small blood vessels by the sickled red blood cells.

Patients present with pain that is often acute in onset but can be insidious. Common locations of pain include extremities, chest, and back. Cold weather, dehydration, hypoxia, and extreme physical stress can precipitate VOC in patients with SCD. In addition to a pain crisis, VOC can manifest as acute chest syndrome (ACS), dactylitis, priapism, stroke, or renal infarction.

Diagnosis: VOC is a clinical diagnosis, with no confirmatory diagnostic tests. Careful history and physical examination are needed to make the diagnosis. Additional differential diagnoses of acute pain in patients with SCD and actions to take to evaluate for acute vaso-occlusive complications are noted below:

• Chest pain: Evaluate for ACS in patients with chest pain and fever or other respiratory symptoms.

• Headache: Perform a thorough neurologic exam to evaluate for stroke

• Flank pain or hematuria: Consider renal papillary necrosis or obstruction by clot

• Abdominal pain: Consider splenic sequestration or gallstones

• Persistent pain (especially bony point tenderness) and fever: Although severe VOC and resultant necrosis of bone can result in fever, persistent pain and fever should raise concern for osteomyelitis.

Management of VOC Pain:

• Opioids

  • Consensus guidelines currently recommend initiation of parenteral analgesic therapy (intravenous [IV] preferred but subcutaneous and intranasal may be alternatives while awaiting IV-line placement) with opioids within 60 minutes of arrival at the medical care facility.

  • When possible, choice and dose of opioids should be tailored to the patient’s personal history of baseline opioid therapy, tolerance, and side effects. Common opioid choices include morphine or hydromorphone. Individualized care plans should be utilized, when available.

  • Opioid doses can be initially administered more frequently to achieve adequate analgesia (with reassessments every 30 to 60 minutes), paying close attention to patients’ neurological and respiratory status to avoid oversedation.

  • If adequate analgesia is not achieved after initial outpatient or emergency room management of VOC, patients should be admitted to the hospital for continued parenteral opioid therapy.

  • Scheduled around-the-clock opioid administration has been shown to be superior to on-demand opioid doses.

  • Unless the patient is exhibiting signs of central nervous system and respiratory depression, opioid doses should be titrated upward by 25% if adequate analgesia is not achieved despite scheduled, around-the-clock parenteral opioid therapy.

  • If no improvement is achieved despite around-the-clock scheduled intermittent dosing of opioids, continuous opioid administration (patient-controlled analgesia or PCA) should be considered.

  • Opioids should be titrated down as VOC resolves rather than stopped abruptly.

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

  • If NSAIDs are not contraindicated, this therapy should be instituted (oral or IV) for the initial 5−7 days of VOC episode.

  • Monitor renal function due to risk for acute kidney injury in VOC, along with other potential adverse effects (including gastrointestinal toxicity).

• Supportive care

  • Encourage incentive spirometry (younger patients could be encouraged to blow bubbles) to reduce risk of ACS during VOC treatment.

  • Monitor frequency of bowel movements. To prevent constipation, consider adding laxatives as needed when initiating scheduled opioids (regardless of the method of administering opioids).

  • Encourage ambulation and activity as soon as possible.

  • If the patient is unable to take oral fluids, use IV fluids for hydration; however, avoid fluid overload, which can place the patient at risk for ACS.

  • In children, pharmacologic approaches can be augmented with nonpharmacologic measures (heat packs and distraction techniques). Of note, ice packs are contraindicated as they would promote sickling.

Note: Red-cell transfusions should not be used for management of VOC, unless other indications for transfusion are present.

Acute Chest Syndrome

Acute chest syndrome (ACS) is the second most common reason for hospitalization in pediatric and adolescent patients with SCD. It is characterized by the presence of a new pulmonary infiltrate with respiratory signs or symptoms.

Etiologies of ACS include, but are not limited to:

• infection (viral, bacterial, chlamydia, or mycoplasma)

• bone-marrow fat embolism (during the first several days of a VOC episode)

• thromboembolism

• intrapulmonary sickling of red blood cells

Presentation:

• Children with ACS usually present with symptoms and signs similar to pneumonia — fever, cough, chest pain, increased work of breathing (retractions, grunting, tachypnea), wheezing, hypoxia — in addition to a new pulmonary infiltrate on chest x-ray.

• ACS is commonly defined by clinical criteria, including the presence of a new infiltrate on imaging plus any two of the following:

  • pleuritic chest pain

  • hypoxemia

  • tachypnea

  • fever

• Because the infiltrate may not be evident on initial chest x-ray, ACS should not be ruled out in a patient presenting with concerning signs or symptoms.

Evaluation and management:

• Initial evaluation for ACS should include history and physical examination, assessment of vital signs (including oxygen saturation), complete blood count with reticulocyte count, and chest x-ray.

• Patients with ACS, or suspected ACS, should be managed as inpatients.

• Initiate antibiotic therapy, including both a cephalosporin (e.g., IV ceftriaxone) and a macrolide (e.g., oral azithromycin) if a diagnosis of ACS has been established to cover for common pathogens that cause infections in this population:

• Administer supplemental oxygen to maintain normal oxygen saturation.

• Administer simple red-cell transfusion: NHLBI consensus statement recommends packed red-cell transfusions in patients with ACS and hemoglobin that has dropped <1.0 g/dL below baseline to increase the oxygen-carrying capacity and decrease the percentage of sickled red cells. (If the baseline Hb is 9 g/dL or greater, transfusion may not be required). Regardless, practice should rely on physician experience and clinical decision.

  • Transfusion goals in SCD should be no higher than 10 g/L to avoid hyperviscosity and resulting stroke. Patients with SCD have more viscous blood than patients without SCD at the same hemoglobin level.

• In the setting of a worsening clinical picture in a patient with ACS (suggested by increasing respiratory effort and oxygen requirements, along with worsening opacities on chest x-ray) despite simple blood transfusions, consider an urgent exchange transfusion (with central line placement if necessary) and close monitoring in an intensive care unit.

• Strongly encourage Incentive spirometry while the patient is awake.

• Monitor closely for signs and symptoms of progression to multi-organ failure, thromboembolism, or both.

Fever

Due to reduced or absent splenic function, patients with SCD are at an increased risk of infections, particularly with encapsulated organisms such as Streptococcus pneumoniae. While prophylactic penicillin administration and pneumococcal vaccination (see Preventive Care in Sickle Cell Disease) have substantially reduced this risk, SCD patients with fever should be treated as having a medical emergency.

Management of fever:

• History, physical examination, and vital sign assessment

• Laboratory investigation:

  • complete blood count with differential

  • reticulocyte count

  • blood culture

  • urine culture (if clinically indicated)

  • chest x-ray (if patient has respiratory symptoms)

• Antibiotic therapy: All SCD patients with fever should receive a parenteral dose of a cephalosporin (e.g., ceftriaxone or clindamycin if allergic) once blood cultures have been obtained. Parenteral antibiotic therapy should be continued if the patient is admitted to the hospital.

• Disposition: While the approach varies by institution, in general a patient with SCD can be discharged after initial management as outlined above, unless high-risk features are identified. The following characteristics suggest higher-risk features and should prompt consideration for inpatient observation pending preliminary results of blood cultures:

  • previous history of bacteremia or pneumococcal sepsis

  • surgical splenectomy

  • fever >103.1° F (39.5° C) with vital sign instability, ill appearance, or both

  • ACS or splenomegaly on physical exam

  • age <6 months

  • lack of transportation, concern for nonadherence to medical recommendations, or other social concerns

• NHLBI consensus guidelines recommend continued inpatient management for administration of parenteral antibiotics in children with a temperature ≥103.1° F (39.5° C) or in those who are ill-appearing. However, institutions vary in the management of patients with SCD and fever.

Stroke

Patients with SCD are at increased risk for stroke due to chronic sickling in cerebral vasculature, occlusion of blood vessels, and associated endothelial damage. Stroke should be strongly considered in patients with SCD who present with severe headaches, aphasia, altered level of consciousness, seizures, paralysis, or other concerning neurologic findings. Annual screening transcranial Doppler (TCD) ultrasonography is recommended in patients ages 2−16 years with SCD to detect those at high risk of stroke (see Preventive Care in Sickle Cell Disease).

Management of stroke:

• Perform prompt history and physical examination, including thorough neurologic exam.

• Consider stroke/neurology consult early in the course.

• Perform urgent computed tomography (CT), followed by magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA).

• Perform urgent blood transfusion, ideally within 2 hours of symptom recognition. When possible, exchange transfusion should be performed in patients with acute neurological defects including transient ischemic attack. If exchange transfusion is not available within 2 hours, simple transfusion should be performed while preparing for manual exchange transfusion.

• In patients who have had a previous stroke, initiate chronic transfusions (with iron chelation to prevent iron overload) for secondary stroke prevention (see Preventive Care in Sickle Cell Disease).

Splenic Sequestration

Splenic sequestration is characterized by an acute enlargement of the spleen in a patient with SCD that is associated with a sudden drop in hemoglobin concentration. Patients often present with thrombocytopenia and reticulocytosis (elevated reticulocyte count). Reticulocytopenia along with a sudden drop in hemoglobin should raise suspicion for aplastic crisis. Splenic sequestration is more common in patients aged 1-4 years with HbSS and HbSβ⁰-thalassemia because autoinfarction of the spleen usually occurs following that age. However, in patients with HbSC and HbSβ⁺-thalassemia, splenic autoinfarction doesn’t occur until later in childhood or even early adult years, therefore these patients may present with splenic sequestration at an older age.

Management of splenic sequestration:

• History and physical examination, with careful palpation for the spleen and vital sign assessment as patients can present in hypovolemic shock due to massive sequestration of red blood.

• IV fluid administration to maintain hemodynamic status in patients presenting in hypovolemic shock (while being cautious to avoid fluid overload and associated ACS)

• Simple red-cell transfusion: Transfusions should be started with smaller volumes (e.g., 5 mL/kg) to avoid over-transfusion due to auto-release of sequestered cells in the spleen.

Preventive Care in Sickle Cell Disease

In addition to routine childhood preventive care, children with SCD require certain additional interventions to screen for and prevent complications. The following table highlights some of the NHLBI recommendations for preventive care in children with SCD.

Preventive Treatment

Hydroxyurea therapy: Hydroxyurea is a ribonucleotide reductase inhibitor that is given to patients with SCD to raise levels of fetal hemoglobin; fetal hemoglobin is mainly produced during fetal life and declines following birth. Patients with SCD who have naturally higher levels of fetal hemoglobin have a less severe clinical course. In addition to other actions, hydroxyurea increases fetal hemoglobin levels and decreases white blood cell count and platelets (see figure below). Hydroxyurea is associated with lower rates of sickle cell-related complications (including pain crises, dactylitis, and ACS). Hydroxyurea is generally safe for use in children and should be offered to all infants with SCD beginning at 9 months of age, including those who are asymptomatic. Additional details on hydroxyurea therapy in the management of patients with SCD can be found in this review article. Despite its favorable impact on survival and pain in SCD, there has unfortunately been suboptimal uptake of hydroxyurea therapy at the population level.

(Source: Hydroxyurea for the Treatment of Sickle Cell Anemia. N Engl J Med 2008.)

Additional Therapies for SCD

Blood or bone-marrow transplantation (BMT): At this time, the only approved cure for SCD is allogeneic transplantation from donors with either sickle cell trait or normal alleles. Although disease-free survival for patients with HLA-matched sibling donors tops 90%, only 20% of SCD patients have such a donor. Nevertheless, substantial complications are associated with allogeneic transplantation with or without an HLA-matched donor as well as the agents required for bone marrow conditioning prior to transplant.

Newer agents for management of SCD:

• Voxelotor is an HbS polymerization inhibitor that has been shown to increase baseline hemoglobin and reduce hemolysis in patients with SCD (HbSS, HbSC, HBS-beta thalassemia and other variants). Voxelotor did not result in a significant difference in the annual incidence rate of VOC in the clinical trial that led to its approval by the FDA in 2019.

• Crizanlizumab is an antibody against adhesion molecule P-selectin (which is upregulated on endothelial cells and platelets and promotes VOC and pain crises). Crizanlizumab was associated with a 45% lower rate of median crises per year when compared to placebo, along with longer time to first and second crises. Crizanlizumab was approved by the FDA in 2019.

• L-glutamine reduces oxidative stress within sickle cell erythrocytes and has been shown to reduce the incidence of pain crises in patients with SCD and HbSβ⁰-thalassemia, along with lower rates of hospitalization when compared to placebo.