Hemoglobinopathies

Anemia with reticulocytosis—moderate to severe in SS and Sβ ⁰ -thalassemia, milder with SC or Sβ ⁺ -thalassemia.

Mean corpuscular volume (MCV) is normal with SS and microcytic with concomitant α-thalassemia; MCV is also microcytic with Sβ-thalassemia and SC genotypes.

Neutrophilia is common.

Platelet count often increased.

Blood smear—sickle cells (not infants or others with high HbF), increased polychromasia, nucleated red cells, and target cells (Howell–Jolly bodies may indicate hyposplenism).

Erythrocyte sedimentation rate—usually low despite inflammation (sickle cells fail to form rouleaux).

Hemoglobin electrophoresis—HbS migrates slower than hemoglobin A. Newborn screening shows FS, FSC, or FSA pattern depending on genotype.

Vaso-occlusive pain event (VOE)

• a.

  Episodic microvascular occlusion at one or more sites resulting in pain and inflammation. Common locations and manifestations of VOE are shown in Table 9.2 . Symptoms of fever, erythema, swelling, and focal bone pain may accompany VOE, making it difficult to distinguish from osteomyelitis. Unfortunately, no test clearly distinguishes these two entities, but Table 9.3 describes clinical, laboratory, and radiographic features that may be helpful in differentiating bone infarction from osteomyelitis.

  Table 9.2

  Common location of vaso-occlusive pain.

  Site	Manifestations
  Hands/feet (dactylitis)	Most common in children younger than 3 years old. Painful swelling of the hands and/or feet. Often can be managed with acetaminophen or nonsteroidal antiinflammatory medication. Unusual in older children because as the child ages, the sites of hematopoiesis move from peripheral locations such as the fingers and toes to more central locations such as arms, legs, ribs, and sternum.
  Bone	More common after age 3 years. Often involves long bones, sternum, ribs, spine, and pelvis. May involve more than one site during a single episode. Swelling and erythema may be present. May be difficult to differentiate from osteomyelitis because clinical symptoms, laboratory studies, and radiological imaging may be similar. Features that may aid in distinguishing these two diagnoses are shown in Table 9.3 .
  Abdomen	Caused by microvascular occlusion of mesenteric blood supply and infarction in the liver, spleen, or lymph nodes that result in capsular stretching. Symptoms of abdominal pain and distension mimic acute abdomen.

  Table 9.3

  Differentiation between bone infarction and osteomyelitis.

  Features	Favoring osteomyelitis	Favoring vaso-occlusion
  History	No previous history	Preceding painful crisis
  Pain, tenderness, erythema, swelling	Single site	Multiple sites
  Fever	Present	Present
  Leukocytosis	Elevated band count (>1000/mm 3 )	Present
  Erythrocyte sedimentation rate	Elevated	Normal to low
  Magnetic resonance imaging	Abnormal	Abnormal
  Bone scan a	Abnormal 99m Tc-diphosphonate	Abnormal 99m Tc-diphosphonate
  	Normal 99m Tc-colloid marrow uptake	Decreased 99m Tc-colloid marrow uptake
  Blood culture	Positive ( Salmonella , Staphylococcus )	Negative
  Recovery	Only with appropriate antibiotic therapy	Spontaneous

  a Obtained within 3 days of symptom onset.

• b.

  The average rate of VOE prompting medical evaluation in SCD-type SS is 0.8 events/year. Approximately 40% of patients never seek medical attention for pain, while about 5% of patients account for a third of all VOE. These numbers underestimate the true incidence of VOE because many episodes are managed at home.

• c.

  Risk factors for pain include high baseline hemoglobin level, low hemoglobin F levels, nocturnal hypoxemia, and asthma.

• d.

  Evidence-based guidelines for the management of VOE are lacking. The typical approach to pain management involves a stepwise progression, beginning with a nonsteroidal anti-inflammatory pain medication for mild-to-moderate pain and adding an opioid pain medication rapidly if pain is not resolving or for moderate-to-severe pain. Rapid alleviation of VOE pain is a basic tenet of SCD management ( Table 9.4 ).

  Table 9.4

  Management of vaso-occlusive pain episodes.

  Setting	Management recommendations
  Home	Ibuprofen and/or acetaminophenIf continued pain, add oral opioid: mild pain—codeine moderate pain—oxycodone, hydrocodone, morphine Supportive measures: heating pad fluids stool softeners and/or laxative if taking opioids for >1–2 days If pain persists or worsens, patient should be evaluated and treated in an acute care setting
  Emergency department or acute care unit	Rapid triage and administration of pain medicationIf no pain medications were taken prior to arrival and pain not severe, may use ibuprofen and oral opioidIf prior pain medications were taken or pain is severe ketorolac tromethamine (NSAID) IV opioid Fluids to maintain euvolemia. IV normal saline bolus should only be used if evidence of decreased oral intake/dehydration
  Inpatient	Continue nonsteroidal antiinflammatory agentContinue IV opioids. Should be given as scheduled medication rather than “as needed”Consider patient-controlled analgesia pump if pain not adequately controlledConsider addition of long-acting opioid (e.g., sustained-release morphine)Ongoing evaluation of adequacy of pain control is essential—utilize pain scalesSupportive care Fluids (oral+IV) to maintain euvolemia Incentive spirometry Heating pad—must be used carefully to avoid burns Bowel regimen to prevent/treat constipation secondary to opioid use Stool softeners (e.g., docusate) Laxative (e.g., senna) Antihistamines (e.g., diphenhydramine, hydroxyzine) for pruritis Venous thromboembolism prophylaxis if mobility limited (age 12 years and older, serial compression devices, low molecular weight heparin if indicated) Transition to oral nonsteroidal and oral opioid as pain level improves

  Abbreviations: IV , Intravenous; NSAID , nonsteroidal antiinflammatory drug.

• e.

  Additional therapies under investigation for the treatment of acute VOE include recombinant ADAMTS13, intravenous (IV) immunoglobulin, and inhaled nitrous oxide.

• f.

  Treatments to reduce VOE rates:

  • i.

    Hydroxyurea (HU).

  • ii.

    Prophylactic red cell transfusions.

  • iii.

    Crizanlizumab was approved by the FDA in 2019 for the prevention of VOE in SCD patients 16 years and older. It is a humanized anti-P-selectin antibody given at a dose of 5 mg/kg intravenously every 4 weeks (following an initial loading period). Crizanlizumab reduced annual VOE rates by approximately 50%, and patients concurrently on HU were more likely to be VOE-free over the study period.

Acute chest syndrome (ACS)

• a.

  ACS is the most common cause of death and the second most common cause of hospitalization in children with SCD. It is generally defined as the development of a new pulmonary infiltrate accompanied by symptoms, including fever, chest pain, tachypnea, cough, hypoxemia, and wheezing.

• b.

  ACS is caused by infection, infarction, and/or fat embolization and iatrogenically by overhydration. About 50% of ACS events are associated with infections, including viruses, atypical bacteria, including Mycoplasma and Chlamydia , and less frequently with Streptococcus pneumoniae . Parvovirus B19 infection can also result in ACS. In about half of cases, ACS develops during hospitalization, often for vaso-occlusive pain, where fat embolization, hypoventilation, and iatrogenic overhydration contribute to the pathophysiology.

• c.

  The incidence of ACS in SCD-SS is about 13 events per 100 patients in children with a peak of about 25 events/100 patients in 2- to 5-year-old patients. The incidence in other sickle cell genotypes is lower (SS>Sβ ⁰ -thalassemia>SC>Sβ ⁺ -thalassemia), and concomitant α-thalassemia does not appear to affect ACS rates.

• d.

  The risk of ACS is directly proportional to the hemoglobin level and white blood cell count; increased levels of cytokines and/or white cell adhesion to the endothelium may play a role. Rates of ACS are also higher in children with asthma. Higher HbF levels appear to be protective.

• e.

  Laboratory findings

  • i.

    White blood cell count is often elevated.

  • ii.

    Hemoglobin level often falls to 1.5 g/dL below baseline values.

  • iii.

    Thrombocytosis may be present and often follows an episode of ACS.

• f.

  The management of ACS is described in Table 9.5 .

  Table 9.5

  Management of acute chest syndrome in children.

  Evaluation

  Chest radiograph Complete blood count and reticulocyte count Blood type and screen Blood culture Viral studies—influenza, respiratory panel, and SARS-COV-2 Pulse oximetry Consider arterial blood gas in room air

  Treatment

  Antibiotics: Broad-spectrum intravenous antibiotic such as ampicillin plus an oral macrolide (erythromycin or azithromycin) to cover atypical bacteria Supplemental oxygen if hypoxemic Fluids: Intravenous+oral fluids should be kept at maintenance. Avoid overhydration Pain control: Must be carefully monitored. Goal is to relieve pain to reduce splinting/poor aeration but avoid oversedation with hypoventilation Transfusion: Simple transfusion (10–15 cm 3 /kg)—do not exceed posttransfusion hemoglobin level of ~10 g/dL Exchange transfusion—if no improvement with simple transfusion or with severe hypoxemia/respiratory distress Bronchodilators—particularly if history of reactive airways disease or if wheezing present Steroids may be beneficial for severe acute chest syndrome or if reactive airways disease component. There is a risk of rebound pain with discontinuation of the steroids Incentive spirometry to reduce atelectasis Mechanical ventilation as needed Consider thoracentesis if significant pleural effusion

• g.

  Prevention of ACS: Patients with a history of recurrent ACS are candidates for preventative/curative therapies, including:

  • i.

    HU.

  • ii.

    Prophylactic red cell transfusions. Optimal target HbS level is not known, but usually a goal of 30–50% is used.

  • iii.

    Hematopoietic stem cell transplantation (HSCT).

Overt stroke

• a.

  Acute symptomatic stroke is usually ischemic in children, although hemorrhagic stroke may occur, particularly in older children and adults.

• b.

  The most common underlying lesion is intracranial arterial stenosis or occlusion, usually involving the large arteries of the circle of Willis, particularly the distal internal carotid artery (ICA), the middle (MCA), and anterior cerebral arteries (ACAs).

• c.

  Chronic injury to the endothelium of vessels by sickled RBCs results in changes in the intima with the proliferation of fibroblasts and smooth muscle; the lumen is narrowed or completely obliterated. Small friable collateral blood vessels known as moyamoya may develop. Infarction of brain tissue occurs acutely as a result of in situ occlusion of the damaged vessel or distal embolization of a thrombus. Perfusional and/or oxygen delivery deficits related to changes in blood pressure or other factors also may contribute to infarction, particularly in watershed zones.

• d.

  Stroke is most common in SCD-SS. Prior to transcranial Doppler (TCD) ultrasound screening with transfusions for high-risk children, stroke prevalence in children with SCD-SS was estimated at 11%, with the highest incidence rates occurring in the first decade of life (1.02 per 100 patient-years in 2- to 5-year olds and 0.79 per 100 patient-years in 6- to 9-year olds). The incidence of first ischemic stroke in the post-STOP era has been reduced to 0.09–0.24 per 100 patient-years.

• e.

  A number of clinical, laboratory, and radiological risk factors for stroke have been identified ( Table 9.6 ).

  Table 9.6

  Factors associated with increased risk of overt infarctive stroke in sickle cell disease.

  Clinical	History of transient ischemic attacks
  	History of bacterial meningitis
  	Sibling with SCD-SS and stroke
  	Recent episode of acute chest syndrome (within 2 weeks)
  	Frequent acute chest syndrome
  	Systolic hypertension
  	Nocturnal hypoxemia
  Laboratory	Low steady-state hemoglobin level
  	No α-gene deletion
  	Certain HLA haplotypes
  Radiological	Abnormal transcranial Doppler ultrasound
  	Silent infarct

  Abbreviations: HLA , Histocompatibility locus antigen; SCD , sickle cell disease.

• f.

  Symptoms of stroke include:

  • i.

    focal motor deficits (e.g., hemiparesis and gait dysfunction),

  • ii.

    speech defects,

  • iii.

    altered mental status,

  • iv.

    seizures, and

  • v.

    headache.

• g.

  Gross neurological recovery occurs in approximately two-thirds of children, but neurocognitive deficits are common.

• h.

  In untreated patients, about 70% of patients experience a recurrence within 3 years. Outcome after recurrent stroke is worse.

• i.

  Any child with SCD who develops acute neurological symptoms requires immediate medical evaluation. The acute management involves prompt diagnosis and treatment and should involve consultation by neurology or a dedicated stroke team.

  • i.

    Diagnosis :

    • Physical examination with detailed neurological examination. Treatment in the setting of clinical suspicion must not await imaging confirmation. Head CT scan is useful for detecting intracranial hemorrhage and often more readily available than magnetic resonance imaging (MRI). CT scan may not be positive for acute infarction within the first 6 hours.

    • Brain MRI with diffusion-weighted imaging is more sensitive to early ischemic changes and may be abnormal within 1 hour. It should be performed as soon as possible in a child with SCD presenting with acute neurological symptoms but should not delay empiric treatment.

    • Magnetic resonance arterial angiography (MRA)—demonstrates large-vessel disease.

  • ii.

    Treatment :

    • Transfusion. Exchange transfusion, either automated or manual, should be performed as soon as possible. The goal is to reduce the amount of HbS to <15–20% and to raise the hemoglobin level to approximately 10 g/dL. If exchange transfusion is not readily available, a simple transfusion to raise the hemoglobin level to no greater than 10 g/dL may be used while awaiting exchange. Exchange transfusion may be associated with a decreased risk of stroke recurrence compared with simple transfusion.

    • Supportive therapy, including avoiding hypotension and maintaining adequate oxygenation and euthermia, should be initiated as adjunctive therapy.

• j.

  Long-term management.

  • i.

    Secondary prophylaxis of recurrent stroke

    • A chronic red cell transfusion program should be instituted, with the goal of maintaining the pretransfusion HbS level at <30%. Transfusions must be continued indefinitely due to the high risk of stroke recurrence after discontinuation of therapy. After a period of 3–4 years after the initial stroke, it may be possible to allow the pretransfusion HbS level to rise to <50% in low-risk patients, without increased risk of stroke recurrence. This approach is associated with decreased transfusional iron loading.

    • HSCT.

    • The uses of revascularization procedures such as encephaloduroarteriosynangiosis or a newer modification, pial synangiosis, may be beneficial in children with significant vasculopathy, particularly if symptomatic (transient ischemic attacks, recurrent stroke).

    • Prophylactic aspirin may also be useful in children with progressive vasculopathy, but the risks of hemorrhage must be weighed against the potential benefit.

    • HU generally is not recommended for secondary stroke prevention. A multicenter phase 3 trial of HU and phlebotomy compared with transfusions and chelation therapy was terminated due to a higher rate of recurrent stroke (10%) in the HU arm compared with continued transfusions (0%) without any difference in iron reduction between the two treatment arms. The stroke recurrence rate on HU still was lower than historical rates in untreated patients; thus HU may be considered in patients who are unable to be transfused, particularly if there is no significant stenosis or occlusion of cerebral blood vessels on MRA.

  • ii.

    Rehabilitation

    • Physical and occupational therapy as needed.

    • Neuropsychological testing should be performed with educational interventions if indicated.

  • iii.

    Screening for stroke risk—primary stroke prevention

    • TCD ultrasonography is a noninvasive study used to measure the blood flow velocity in the large intracranial vessels of the circle of Willis.

    • The highest time-averaged mean velocity (TAMMvel) in the distal ICA, its bifurcation, and the MCA are used to categorize studies into risk groups:

      • ◦

        Normal (velocity <170 cm/s), low risk.

      • ◦

        Conditional (170–199 cm/s), moderate risk.

      • ◦

        Abnormal (≥200 cm/s), high risk.

      • ◦

        Inadequate—unable to obtain velocity in the ICA or MCA on either side, in the absence of a clearly abnormal value in another vessel. Inadequate TCD may be due to technique, skull thickness, or severely stenosed vessel.

      • ◦

        Very low velocity (ICA/MCA velocity <70 cm/s) may indicate vessel stenosis and increased risk of stroke.

    • Elevated velocity in the ACA (>170 cm/s) is associated with increased stroke risk. Treatment of children with isolated high ACA velocities has not been established. Brain MRI/MRA should be obtained. Chronic transfusion should be instituted for children with ACA velocity ≥200 cm/s, and with elevated ACA velocity if there is evidence of significant cerebral blood vessel stenosis on MRA.

    • TCD screening is recommended for children with SCD-SS or SCD-Sβ ⁰ -thalassemia ages 2–16 years. Screening is performed annually, but more frequently if the prior study was not normal. An approach to screening is shown in Table 9.7 . In addition, more frequent screening should be considered if other known stroke risk factors are present (such as sibling with SCD-SS and stroke or abnormal TCD).

      Table 9.7

      Transcranial Doppler ultrasonography screening protocol.

      Last TCD result (TAMMvel in ICA/MCA)	Screening interval
      Normal (<170 cm/s)	Annual
      Low conditional (170–184 cm/s)	3–6 months a
      High conditional (185–199 cm/s)	6 weeks–3 months a
      Abnormal (200–219 cm/s)	1 week
      High abnormal (220 cm/s or higher)	No confirmation needed—recommend treatment

      Abbreviations: ICA , Internal carotid artery; MCA , middle cerebral artery; TCD , transcranial Doppler.

      a Use the shorter time interval for children <10 years old.

    • Brain MRI/MRA should be obtained in children with abnormal TCD and should be considered for children with conditional TCD.

    • Brain MRA is helpful to evaluate cerebral vasculature in children with repeatedly inadequate TCD, with very low velocity, and with isolated elevated velocity in the ACA or posterior cerebral artery.

  • iv.

    Treatment

    • Chronic transfusion to maintain the HbS level <30% reduces the risk of stroke by >90% in children with abnormal TCD.

    • Discontinuation of transfusion therapy without alternative therapy after ≥30 months of transfusion in children whose TCD normalized is not recommended as this was associated with a high risk of reversion to abnormal TCD and stroke.

    • In children with a history of abnormal TCD who have received ≥1 year of red cell transfusions and have no MRA evidence of severe vasculopathy, a switch to HU therapy can be considered.

      • ◦

        The TWITCH trial showed that HU was not inferior to continued transfusions for the control of TCD velocities in that patient population.

      • ◦

        A gradual switch to HU at maximum tolerated dose, with a period of transfusion overlap, typically 6–9 months, is recommended.

      • ◦

        Ongoing monitoring and support of adherence with HU are essential.

    • HSCT with a histocompatibility locus antigen (HLA)-identical sibling donor should be considered.

Priapism

• a.

  Priapism is a sustained, painful erection of the penis. Priapism may be prolonged (lasts >3 hours), or stuttering (lasts <3 hours). Stuttering episodes often recur or may develop into a prolonged episode.

• b.

  Occurs in 30–45% of patients with SCD, most commonly in the SS type. The prevalence is likely underestimated due to underreporting by patients.

• c.

  Mean age at the first episode of priapism in patients with SCD is about 12–15 years; 75% have their first episode before age 20 years.

• d.

  Priapism often occurs in the early morning hours, when normal erections occur, and is probably related to nocturnal acidosis and dehydration. The normal slow blood flow pattern in the penis is similar to the blood flow in the spleen and renal medulla. Failure of detumescence is due to venous outflow obstruction or to prolonged smooth muscle relaxation, either singly or in combination.

• e.

  A history of priapism in childhood is associated with later sexual dysfunction, with 10–50% of adults with SCD and a history of priapism reporting impotence.

• f.

  Treatment

  • i.

    At home, patients may try warm baths, oral analgesics, increased oral hydration, exercise, and pseudoephedrine.

  • ii.

    Patients should be evaluated in an emergency room for episodes lasting over 2 hours.

  • iii.

    Initial treatment includes IV hydration and parenteral analgesia.

  • iv.

    Episodes lasting ≥4 hours are associated with an increased risk of irreversible ischemic injury and thus warrant more aggressive management. Urological consultation should be obtained. Treatment involves aspiration of the corpus cavernosum followed by irrigation with or without intracavernous administration of a dilute (1:1,000,000) epinephrine solution. Although published data in SCD are lacking, a dilute solution of phenylephrine, an alpha-adrenergic agent, rather than epinephrine, has also been utilized in some centers.

  • v.

    Inhaled nitrous oxide (maximum 60%) was associated with detumescence within 4–15 minutes in a case report of two children with priapism; further study is needed.

• g.

  The role of transfusion for the management of priapism is controversial and the clinical response is variable. Furthermore, exchange transfusion for acute priapism has been associated with the development of acute neurological events.

• h.

  Surgical shunting procedures (corpus cavernosum—corpus spongiosum or cavernosaphenous) may be considered if the previous treatments fail, although shunt occlusion is a common complication.

• i.

  Prevention of priapism

  • i.

    Pseudoephedrine, 30–60 mg orally at bedtime.

  • ii.

    HU therapy has been employed, although this treatment has not been studied for this indication.

  • iii.

    Leuprolide injections, a gonadotropin-releasing hormone analog that suppresses the hypothalamic–pituitary access, reducing testosterone production.

  • iv.

    Phosphodiesterase type 5 inhibitors may have some benefit, but studies of sildenafil and tadalafil have been limited; further research is needed.

  • v.

    Transfusion protocol for 6–12 months following an episode of priapism requiring irrigation and injection.

Splenic sequestration

• a.

  Highest prevalence between 5 and 24 months of age in SCD-SS; may occur at older ages in patients taking HU or receiving regular transfusions and with other genotypes (Sβ-thalassemia, SC).

• b.

  May occur in association with fever or infection, including parvovirus B19.

• c.

  Splenomegaly due to pooling of large amounts of blood in the spleen.

• d.

  Rapid onset of pallor and fatigue. Abdominal pain is often present.

• e.

  Hemoglobin level may drop precipitously, followed by hypovolemic shock and death.

• f.

  Reticulocytosis and nucleated RBCs often present.

• g.

  Platelet and white blood cell count also usually fall from baseline.

• h.

  Treatment of splenic sequestration is shown in Table 9.8 .

  Table 9.8

  Management of splenic sequestration.

  Treatment of acute splenic sequestration episode	Monitor cardiovascular status, spleen size, and hemoglobin level closely.
  	Normal saline bolus of 10–20 cm 3 /kg.
  	Red cell transfusion. Administer in small aliquots because transfusion often results in reduction in spleen size with “autotransfusion” of previously trapped red cells. Rapid infusion used for cardiovascular instability.
  	Pain management.
  Prevention of recurrent splenic sequestration	Splenectomy if history of one major or two minor acute splenic sequestration episodes.
  	For children <2 years old, chronic transfusion therapy can be considered to postpone splenectomy, though this may not prevent recurrent episodes.

Transient pure red cell aplasia

• a.

  Cessation of red cell production that may persist for 7–14 days with profound drop in hemoglobin.

• b.

  Reticulocyte count and the number of nucleated red cells in the marrow sharply decrease; platelet and white blood cell counts are generally unaffected.

• c.

  May occur in several members of a family and can occur at any age.

• d.

  Almost invariably associated with parvovirus B19 infection.

• e.

  Terminates spontaneously usually after about 10 days (recovery occurs with reticulocytosis and nucleated red cells in the blood).

• f.

  Vaso-occlusive pain and/or splenic sequestration may occur in association with parvovirus B19/transient pure red cell aplasia.

• g.

  Treatment

  • i.

    close monitoring of complete blood count (CBC) and reticulocyte count,

  • ii.

    red cell transfusion to raise hemoglobin level to no greater than 9–10 g/dL, and

  • iii.

    monitor siblings with SCD closely [CBC, reticulocyte count, parvovirus polymerase chain reaction, and/or titers].

Central nervous system (CNS)

• a.

  Silent cerebral infarction

  • i.

    defined as one or more focal T2-weighted signal hyperintensities demonstrated on brain MRI, in the absence of a focal neurological deficit corresponding to the anatomical distribution of the brain lesion;

  • ii.

    present in approximately 39% of children with SCD-SS and occurs less commonly in other sickle cell genotypes;

  • iii.

    associated with neuropsychological deficits and impaired school performance; and

  • iv.

    silent infarcts may progress in size and number over time and are associated with an increased risk of overt stroke.

• b.

  Management of children with silent infarcts includes neuropsychological testing and monitoring of academic performance.

• c.

  Chronic transfusion therapy to maintain the hemoglobin level above 9 g/dL and the HbS below 30% for children with silent cerebral infarcts is associated with a reduction in infarct recurrence. In a large multicenter trial, new or enlarged silent infarcts or overt stroke occurred in 6% of children receiving transfusions compared with 14% of children in the observation group.

• d.

  HU has not been studied for this indication.

Cardiovascular system

• a.

  Abnormal cardiac findings are present in most patients as a result of chronic anemia and the compensatory increased cardiac output.

• b.

  Cardiomegaly is found in most patients and left ventricular hypertrophy occurs in about 50%.

• c.

  Prolonged QTc>440 ms occurs in 9–38% of children with SCD, most commonly the SS type. Prolonged QTc is associated with increased risk of mortality in adults with SCD.

• d.

  A moderate-intensity systolic flow murmur is often present.

• e.

  Echocardiogram may show left and right ventricular dilatation, increased stroke volume, and abnormal septal motion. Diastolic dysfunction occurs in 11–77% of patients with SCD and is associated with myocardial fibrosis, exercise impairment, and increased risk of mortality.

• f.

  Pulmonary hypertension

  • i.

    Defined as a resting pulmonary artery systolic pressure ≥25 mmHg. Right-heart catheterization is required to make a definitive diagnosis. Noninvasive echocardiography often is used to screen for the possible presence of pulmonary hypertension. Tricuspid regurgitant jet velocity (TRV) of ≥2.5 m/s is an indicator of possible pulmonary hypertension.

  • ii.

    Prevalence of pulmonary hypertension documented by right-heart catheterization in adults is estimated at 6–11%, with 10% of these adults having moderate-to-severe pulmonary hypertension (pressure above 45 mmHg). An elevated TRV is found in approximately 30% of adults with SCD. The prevalence of elevated TRV in children appears to be about 11% and is most common with the SS genotype. Diagnosis of pulmonary hypertension by TRV alone has been questioned. Children with elevated TRV should be managed along with a cardiologist.

  • iii.

    In adults, pulmonary hypertension by right-heart catheterization, elevated TRV, and increased serum N-terminal probrain natriuretic peptide are independent risk factors for mortality; the significance of these findings in children is unclear.

  • iv.

    A central role for hemolysis and altered NO bioavailability has been postulated.

  • v.

    The optimal treatment is unknown, but HU or red cell transfusions have been used. Treatment with sildenafil, an agent used to treat pulmonary hypertension in other patient groups, is associated with an increased risk of vaso-occlusive pain episodes.

Pulmonary

• a.

  Reduced PaO ₂ .

• b.

  Reduced O ₂ saturation. Pulse oximetry may not correlate with PaO ₂ in steady state. Changes in pulse oximetry are useful for monitoring children with ACS. Daytime and/or nocturnal hypoxemia may be present.

• c.

  Chronic lung disease—pulmonary fibrosis: This is a prime contributor to mortality in young adults with SCD.

  • i.

    Early identification of progressive lung disease using pulmonary function testing is imperative. Aggressive treatment has little benefit in end-stage lung disease and this should be avoided by prophylactic transfusions.

  • ii.

    The staging system for chronic lung disease is based on clinical, physiological, and radiographic criteria, with progression from stage to stage every 2–3 years.

    • Stage 1 is characterized by a mild reduction in lung volumes (vital capacity and total lung capacity) and forced expiratory volume in 1 s /forced vital capacity (FVC) ratio (defines airflow obstruction).

    • Stage 2 is characterized by moderate reduction in these measurements.

    • Stage 3 is where hypoxemia is first observed during stable periods, and a severe reduction in lung volumes and flows is seen with associated borderline pulmonary hypertension and fibrosis on chest radiograph.

    • Stage 4 is characterized by severe pulmonary fibrosis and pulmonary hypertension

• d.

  Asthma—prevalence appears to be higher than in general population in children with SCD. Asthma is associated with complications of SCD, including pain, ACS, stroke, and pulmonary hypertension. Aggressive management is warranted. Using steroid for asthma exacerbations may lead to rebound VOE.

Renal

• a.

  Increased renal flow and glomerular filtration rate.

• b.

  Enlargement of kidneys; distortion of collecting system.

• c.

  Hyposthenuria (urine concentration defect): Hyposthenuria is the first manifestation of sickle cell–induced obliteration of the vasa recta of the renal medulla. Edema in the medullary vasculature is followed by focal scarring, interstitial fibrosis, and destruction of the countercurrent mechanism. Hyposthenuria results in a concentration capacity of >400–450 mOsmol/kg and an obligatory urinary output as high as 2000 mL/m ² per day, causing the patient to be particularly susceptible to dehydration. The increased urine output is associated with nocturia, often manifesting as enuresis. The treatment of nocturnal enuresis includes behavioral modifications and 1-deamino-8- d -arginine vasopressin at bedtime.

• d.

  Hematuria: Papillary necrosis is usually the underlying anatomic defect. The treatment of papillary necrosis is IV hydration and rest. Frank hematuria usually resolves, although bleeding can be prolonged. Antifibrinolytic agents such as epsilon-aminocaproic acid have been used for recalcitrant bleeding with variable success. However, caution must be taken when using this drug because of the risk of thrombosis and urinary obstruction. Evaluation for other causes of hematuria (e.g., renal medullary carcinoma) is indicated for the first episode of hematuria.

• e.

  Renal tubular acidification defect.

• f.

  Increased urinary sodium loss (may result in hyponatremia).

• g.

  Hyporeninemic hypoaldosteronism and impaired potassium excretion are results of renal vasodilating prostaglandin increase in patients with SCD.

• h.

  Proteinuria: Persistent increasing proteinuria is an indication of glomerular insufficiency, perihilar focal segmental sclerosis, and renal failure. Intraglomerular hypertension with sustained elevations of pressure and flow is the prime etiology of the hemodynamic changes and subsequent proteinuria. If proteinuria persists for >4–8 weeks, angiotensin-converting enzyme inhibitors (i.e., enalapril) are recommended.

• i.

  Nephrotic syndrome: A 24-hour urine protein of >2 g/day, edema, hypoalbuminemia, and hyperlipidemia may indicate progressive renal insufficiency. The efficacy of steroid therapy in the management of nephrotic syndrome in SCD is not clear. Carefully monitored use of diuretics is indicated to control edema.

• j.

  Chronic renal failure and uremia.

Liver and biliary system

• a.

  Chronic hepatomegaly.

• b.

  Liver function tests: Increased serum aspartate transaminase and serum alanine transaminase.

• c.

  Cholelithiasis.

  • i.

    Chronic hemolysis with increased bilirubin turnover causes pigmented stones

  • ii.

    Occurs as early as 2 years old and affects ≥30% by age 18 years

  • iii.

    Sonographic examinations of the gallbladder should be performed in children with symptoms

  • iv.

    The treatment for symptomatic cholelithiasis is laparoscopic cholecystectomy. The role of screening and treatment of asymptomatic patients is unclear

• d.

  Transfusion-related hepatitis. Hepatitis C is more common in older patients who received red cell transfusions prior to the availability of screening of blood products.

• e.

  Intrahepatic crisis: Intrahepatic sickling can result in massive hyperbilirubinemia, elevated liver enzyme values, and a painful syndrome mimicking acute cholecystitis or viral hepatitis. Progression to multiorgan system failure may occur. Early exchange transfusion is indicated.

• f.

  Hepatic necrosis, portal fibrosis, regenerative nodules, and cirrhosis are common postmortem findings that may be a consequence of recurrent vascular obstruction and repair.

• g.

  Transfusional iron overload, secondary to repeated intermittent or chronic transfusions, may cause hepatic fibrosis.

Bones

• a.

  Skeletal changes in SCD are common because of expansion of the marrow cavity, bone infarcts, or both.

• b.

  Widening of medullary cavity and cortical thinning: Hair-on-end appearance of skull on radiograph.

• c.

  Fish-mouth vertebra sign on radiograph.

• d.

  Avascular necrosis (AVN):

  • i.

    SCD is the most common cause of AVN of the femoral head in childhood. AVN of the humeral head is less common.

  • ii.

    The cumulative incidence rate for AVN of the femoral head in SCD is estimated at 22%.

  • iii.

    The incidence is higher with coexistent α-thalassemia, in patients who have frequent painful events, history of ACS, and in those with the highest hematocrits.

  • iv.

    The pathophysiology is due to repeated ischemia–reperfusion injury of vulnerable articular surfaces.

  • v.

    About 50% of patients are asymptomatic. Symptomatic patients have significant chronic pain and limited joint mobility.

  • vi.

    The diagnosis is made radiographically and shows subepiphyseal lucency and widened joint space, flattening or fragmentation and scarring of the epiphysis. AVN of femoral head can be detected by MRI before deformities are apparent on radiograph.

  • vii.

    AVN of the hip may have its onset in childhood, so thorough musculoskeletal examination with concentration on the hips should be performed at least yearly in children with SCD.

  • viii.

    Progression of early-stage AVN of the femoral hip to collapse is extremely common.

    • Spontaneous regression of AVN in some typically younger children has been reported.

  • ix.

    Treatment:

    • Therapy for AVN is largely supportive, with bed rest, nonsteroidal antiinflammatory drugs, and limitation of movement during the acute painful episode.

    • Transfusion therapy and HU do not seem to delay the progression of AVN.

    • Physical therapy is helpful and may reduce the risk of progression.

    • Core decompression of the affected hip has been reported to reduce pain and stop progression of the disease. In this procedure, avascularized bone is removed to decompress the area with the potential for subsequent new bone formation. This procedure seems to be beneficial only in the early stages of AVN and before loss of the integrity of the femoral head.

    • Total hip replacement: Recent data show favorable outcomes and improved quality of life using cementless grafts. Careful perioperative management, including appropriate hydration, transfusion, antibiotics, and pain management, are needed.

Eyes

• a.

  Retinopathy: Sickle retinopathy is common in all forms of SCD, but particularly in those patients with SCD, type SC.

  • i.

    Nonproliferative: Occlusion of small blood vessels of the eye detected on the dilated ophthalmological examination and usually not associated with defects in visual acuity. Treatment is usually not needed.

  • ii.

    Proliferative: Occlusion of small blood vessels in the peripheral retina may be followed by enlargement of existing capillaries or the development of new vessels. Clusters of neovascular tissue “sea fans” grow into the vitreous and along the surface of the retina. Sea fans may cause vitreous hemorrhage, which results in transient or prolonged loss of vision. Small hemorrhages resorb but repeated leaks cause the formation of fibrous strands. Shrinkage of these strands can cause retinal detachment.

  • iii.

    Treatment: In proliferative retinopathy, neovascularization may not progress or may regress spontaneously. Indications for treatment include bilateral proliferative disease, rapid growth of neovascularization, and large elevated neovascular fronds. Laser photocoagulation and other methods are used to induce regression of neovascularization.

  • iv.

    Screening: With proper screening and new methods such as laser surgery, most of the complications of retinopathy can be avoided. Annual ophthalmologic examinations, including inspection of the retina, are indicated for children from the age of 5 years for children with SCD-SC and 8 years for children with SCD-SS.

  • v.

    Patients should be instructed to seek medical attention for new vision changes, flashing lights, or new visual floaters.

• b.

  Angioid streaks: These are pigmented striae in the fundus caused by abnormalities in the Baruch membrane due to iron or calcium deposits or both. They usually produce no problems for the patient, but occasionally they can lead to neovascularization that can bleed into the macula and decrease vision.

• c.

  Hyphema: Blood in the anterior chamber (hyphema) rarely occurs secondary to sickling in the aqueous humor, because of its low pH and pO ₂ . Traumatic hyphema may occur as in any individual. Anterior chamber paracentesis should be performed if pressure is increased.

• d.

  Conjunctivae: Comma-shaped blood vessels, seemingly disconnected from other vasculature, can be seen in the bulbar conjunctiva of patients with SCD and variants (SS>SC>Sβ-thalassemia). These produce no clinical disability. Their frequency may be related to the number of irreversibly sickled cells in the blood. This abnormality can be identified by using the +40 lens of an ophthalmoscope.

Ear, nose, and throat

• a.

  Sensorineural hearing loss. Up to 12% of pediatric patients have high-frequency sensorineural hearing loss, and as high as 30% of adults in some studies. The pathophysiology may involve sickling in the cochlear vasculature with destruction of hair cells.

• b.

  Adenotonsillar hypertrophy giving rise to upper airway obstruction can become a problem from the age of 18 months. The marked hypertrophy is postulated to be compensation for the loss of lymphoid tissue in the spleen. It occurs in ≥18% of patients and up to 50% in some studies. In severe cases, this can cause hypoxemia at night with consequent sickling and should be evaluated with a sleep study. Early tonsillectomy and adenoidectomy may be indicated in these patients.

Skin

• a.

  Cutaneous ulcers of the legs occur over the external or internal malleoli. Leg ulcers occur less commonly in children, and rarely before age 10 years. Ulcers are most common in homozygous SCD. Ulceration may result from increased venous pressure in the legs caused by the expanded blood volume in the hypertrophied bone marrow.

• b.

  Treatment includes rest and elevation, physical protection with soft sponge-rubber doughnut, debridement and scrupulous hygiene, elastic stockings to improve venous circulation, and oral administration of zinc sulfate. If ulcers persist despite optimal care, consider transfusion therapy for 3–6 months. More severe cases can require split-thickness skin grafts.

Growth and development

• a.

  Growth delay:

  • i.

    Birth weight is normal.

  • ii.

    By 2–6 years of age the height and weight are significantly delayed. The weight is more affected than the height, and patients with SCD-SS and Sβ ⁰ -thalassemia experience more delay in growth than patients with SCD-SC and Sβ ⁺ -thalassemia.

  • iii.

    By the end of adolescence, patients with SCD have caught up with controls in height but not weight. The poor weight gain is likely to represent increased caloric requirements in anemic patients with increased bone marrow activity and cardiovascular compensation.

  • iv.

    Growth hormone levels and growth hormone stimulation studies appear to be normal in most children who have impaired growth.

• b.

  Delayed sexual maturation: Tanner 5 is not achieved until the median ages of 17.3 and 17.6 years for girls and boys, respectively. In males, decreased fertility with abnormal sperm motility, morphology, and numbers is prominent.

• c.

  Zinc deficiency may contribute to poor growth and delays in sexual maturity; supplementation with elemental zinc, 10 mg daily, was associated with improved linear growth and weight gain in a pilot study of children ages 4–10 with SCD-SS.

Functional hyposplenism

• a.

  By 6 months of age, mild splenomegaly may be apparent and persists during early childhood, after which the spleen undergoes progressive fibrosis (autosplenectomy).

• b.

  Functional reduction of splenic activity occurs in early life due to altered intrasplenic circulation caused by intrasplenic sickling. It can be temporarily reversed by transfusion of normal red cells.

• c.

  Children with functional hyposplenia are 300–600 times more likely to develop overwhelming pneumococcal and Haemophilus influenzae sepsis and meningitis than are healthy children; other organisms involved are Gram-negative enteric organisms and Salmonella . The period of greatest risk of death from severe infection occurs during the first 5 years of life.

• d.

  Functional hyposplenism may be demonstrated by the following:

  • i.

    the presence of Howell–Jolly bodies on blood smear,

  • ii.

    ^99m Tc-gelatin sulfur colloid spleen scan—no uptake of the radioactive colloid by enlarged spleen, and

  • iii.

    pitted RBC count >3.5%.