What is sickle cell disease?

Sickle cell disease (SCD) is a genetic disorder of haemoglobin synthesis.

Haemoglobin is a tetramer comprised of four polypeptide globin chains, each containing a haem molecule (which reversibly binds oxygen). Beyond infancy, adult haemoglobin (HbA) replaces foetal haemoglobin (HbF) as the predominant haemoglobin molecule. HbA consists of two alpha and two beta globin chains. 

SCD is caused by a point mutation in the beta globin gene resulting in a structurally abnormal haemoglobin molecule, HbS. 

The primary event in sickle cell pathology is polymerisation of HbS, distorting the red cell shape and leading to the characteristic sickle appearance.  Polymerisation can occur in the setting of deoxygenation, acidosis, pyrexia and dehydration. Recurrent episodes of sickling cause red blood cell (RBC) membrane damage and an irreversibly sickled cell.

Sickled RBCs adhere to the vascular endothelium and circulating RBCs causing occlusion of the microvascular circulation (vaso-occlusion). Sickled RBCs also undergo haemolysis, with an average RBC lifespan of only 17 days.

The physiological changes in RBCs result in a multisystem disease with the following key features:

• Chronic haemolytic anemia
• Painful vaso-occlusive episodes
• Multi-organ damage from micro-infarcts (including cardiac, skeletal, splenic and central nervous system).

Inheritance and incidence

Sickle cell anaemia is inherited in an autosomal recessive pattern.

It is one of the most common, severe monogenic disorders worldwide. The prevalence of the disease is high among individuals of sub-Saharan African, Indian, Saudi Arabian and Mediterranean descent. 

It is estimated that 312 000 neonates are born with sickle cell anaemia globally each year, over 75% of whom are born in sub-Saharan Africa.

Terminology

SCD refers to a group of disorders characterised by the presence of at least one HbS allele in addition to a second beta globin gene mutation. 

In sickle cell anaemia, individuals are homozygous for HbS (HbSS). This is the most frequent and severe form of the disease. Other variants of SCD include sickle β thalassaemia (HbSβ⁰ or HbSβ⁺ thalassaemia) and haemoglobin SC disease (HbSC)

Individuals with sickle cell trait are benign carriers for the condition, inheriting HbS and a normal beta globin gene (HbAS). Sickle cell trait confers a survival advantage in malaria endemic areas. 

Diagnosis

Universal newborn screening for SCD has been implemented in the United States and United Kingdom. SCD is not part of the newborn screening program in Australia.

SCD can be diagnosed through the identification of haemoglobin variants using haemoglobin electrophoresis, high-performance liquid chromatography (HPLC) or isoelectric focusing. 

Clinical manifestations 

Symptom onset usually occurs within the first year of life, often at around 5 months. The delay in clinical signs and symptoms is due to the higher levels of HbF in infancy preventing the polymerisation of HbS.

Clinical manifestations include:

Anaemia

• Patients have a chronic, compensated haemolytic anaemia.
• Major causes of an acute drop in haemoglobin include splenic sequestration and aplastic crisis. 
• Aplastic crisis is caused by a transient arrest in erythropoiesis. This is typically caused by infection, commonly human parvovirus B19.

Vaso-occlusive pain episodes

• This is the cardinal feature of SCD and accounts for the majority of hospital admissions.
• Acute pain occurs due to ischaemic tissue injury secondary to vaso-occlusion of sickled cells.
• The majority of episodes have no identifiable cause, however common triggers include infection, fever, acidosis, hypoxia, dehydration and exposure to temperature extremes. 
• Common sites of pain include the chest, abdomen, back and extremities. Dactylitis is a common presentation in infants and toddlers, with back and abdominal pain more common in older children.
• Management of vaso-occlusive episodes involves early and aggressive pain relief.

Splenic sequestration 

• Splenic sequestration occurs when large quantities of sickled RBCs pool within the spleen. This is a potentially life threatening complication of SCD, with a risk of hypovolaemic shock.
• Splenic sequestration is characterised by the sudden enlargement of the spleen, an acute drop in haemoglobin (>20 g/L), thrombocytopaenia and an increase in reticulocytes.
• It typically occurs between the ages of 6 months and 2 years.
• Management includes: 
  • Restoration of circulating blood volume with a blood transfusion. This increases the haemoglobin level directly and promotes the release of trapped RBCs by the spleen. 
    • Always discuss transfusion targets with the on-call haematologist, as autotransfusion will occur if haemoglobin is increased excessively or too quickly thereby increasing the risk of hyperviscosity syndrome. 
  • Active fluid resuscitation for hypovolaemia while awaiting a blood transfusion.

Infection

• Functional hyposplenism occurs early in life due to splenic infarction.
• Patients are at an increased risk of invasive bacterial infections, particularly by encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae type B and Neisseria meningitidis).
• Children with SCD presenting with a febrile illness require prompt assessment and empiric IV antibiotics.
• Prevention strategies include: 
  • Prophylactic penicillin for all young children, ideally by the age of 2-3 months. This has been shown to significantly reduce the morbidity and mortality of pneumococcal infections.
  • Vaccinations as per the functional asplenia/hyposplenia guidelines.

Acute chest syndrome (ACS)

• This is the leading cause of mortality in patients with SCD.
• ACS is defined as a new infiltrate on chest x-ray associated with new respiratory symptoms (chest pain, respiratory distress, hypoxia or cough) and/or fever. 
• The majority of patients do not have a single identifiable cause. Possible aetiologies include infection, atelectasis, vaso-occlusion and fat emboli from infarcted bone marrow.
• Management includes supplemental oxygen, IV antibiotics, exchange transfusion, analgesia, physiotherapy and early PICU involvement if hypoxia or respiratory distress.

Stroke

• Prior to routine screening with transcranial doppler ultrasound (TCD), clinically evident strokes occurred in up to 11% of patients with SCD by the age of 20 years.
• Silent cerebral infarcts (evidence of infarction on neuroimaging in the absence of overt neurological symptoms) occur in up to 20% of children with sickle cell anaemia.
• Management includes: 
  • Prompt neuroimaging – MRI is the modality of choice, however if unavailable non-contrast CT should be performed (contrast increases the risk of hyperviscosity).
  • Exchange transfusion.
• Primary prevention strategies include:
  • Regular TCD assessment starting from the age of 2 years. 
  • Prophylactic regular transfusions for children with persistently elevated TCD velocity.

Priapism

• Priapism is an unwanted, persistent erection in the absence of sexual activity.
• The majority of episodes occur due to impaired venous outflow from the penis causing increased pressure, preventing normal arterial circulation.
• Prolonged episodes of priapism (>4 hours) may lead to permanent tissue damage, with a risk of erectile dysfunction.
• The optimal treatment is unknown. 
• Management strategies include hydration, analgesia, oxygen therapy, showering, short aerobic exercise and urination (consider catheterisation if unable to empty bladder). Ice should not be used as cold temperatures may exacerbate sickling. 
• Priapism extending beyond 4 hours is a urological emergency and consultation with the on-call haematologist and general surgical/urology team is required.

Avascular necrosis

• Avascular necrosis occurs at a higher rate in children with SCD.
• It commonly affects the femoral and humeral heads.

Sickle cell disease and COVID-19

There is limited data on the relationship between SCD and COVID-19. Children with sickle cell disease, thalassaemia and rare anaemias without other risk factors do not seem to be at increased risk of having severe disease. 

Emergency department management

Examination

• Vital signs
• Pallor or jaundice
• Hydration status
• Respiratory examination
• Spleen examination, with comparison to baseline
• Neurological examination
• Localising signs of infection

Investigations

• FBE and reticulocyte count
  • Splenic sequestration: haemoglobin below baseline, thrombocytopaenia, reticulocytosis
  • Aplastic anaemia: haemoglobin below baseline, decreased reticulocyte count (<1%)
• Blood group and cross match
• UEC and LFT (if jaundice or dehydrated)
• Based on assessment
  • If febrile 🡪 blood and urine culture
  • If respiratory symptoms 🡪 consider chest x-ray
  • If neurological findings 🡪 urgent neuroimaging

Acute management

• Prompt review and early discussion with the on-call haematologist.
• Aggressive pain management – all patients with SCD presenting with pain should initially be managed as a vaso-occlusive episode, with the exception of chest pain, which should be treated as ACS.
• Oxygen therapy for hypoxia or respiratory distress, aiming for SaO2 >96% or for comfort.
• Fluid management:
  • Encourage oral fluids.
  • Consider IV fluids for fluid resuscitation or maintenance fluids if unable to tolerate oral intake.
  • It is important to recognise that excessive fluid administration can increase the risk of ACS.
• A blood transfusion may be required, however this should always be in consultation with the on-call haematologist to discuss both the type of transfusion and transfusion targets. 
  • There is a risk of hyperviscosity if the haemoglobin is increased significantly over the patient’s baseline.
• If febrile, commence IV antibiotics with a third generation cephalosporin, in addition to atypical coverage if there is a significant respiratory component. 
• If respiratory symptoms, suspect ACS.

Chronic management

Blood transfusions are used to treat and prevent the complications of SCD. Types of transfusions include simple, manual partial exchange and automated red cell exchange (erythrocytapheresis).  

Hydroxyurea is a myelosuppressive agent used in the management of individuals with SCD, which has been shown to reduce the vaso-occlusive complications. 

A life-long cure for SCD is only available through haematopoietic stem cell transplantation.

Prognosis

Individuals with SCD have reduced overall life expectancy. In high-income countries, the survival of individuals with SCD is improving steadily through measures such as newborn screening, early initiation of antibiotic prophylaxis, immunisations and screening for children at high risk of stroke.

This is not the case worldwide. The majority of countries where SCD is a major public health concern lack national programs and key public health interventions. As a result, sickle cell anaemia-related childhood mortality in Africa is as high as 50-90%, with less than half of affected children reaching the age of five. The World Health Organization (WHO) estimates that 70% of sickle cell anaemia deaths are preventable with simple, cost-effective interventions. 

Key messages

References

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