Abigail is a 10-month-old female presenting to the Emergency Department with a history of profound lethargy, pallor and a mildly distended abdomen over the last few hours.
She has no past medical history, her immunisations are up to date, and she has no known allergies. Her parents report that she is usually well. However, they have noticed recent swelling of her hands and feet over the last month. Her parents are originally from Nigeria. In the Emergency Department, she is pale and flat.
She is tachycardic with a heart rate of 180 bpm and afebrile. On examination, she has a prolonged capillary refill time of 5 seconds and cool peripheries. She has a soft systolic murmur. Her spleen measures 7cm below the costal margin, and she squirms on abdominal palpation. There is no history or evidence of trauma.
The team get IV access and sends off some bloods, including venous blood gas, blood culture, FBE, blood group and cross match, LFT and UEC.
She is given a 10ml/kg fluid bolus of 0.9% sodium chloride and commenced on broad-spectrum antibiotics. After a second 10ml/kg bolus, her capillary refill time and heart rate improve, but she is still very lethargic.
After an hour or so, Pathology call you up. Her formal haemoglobin is 64 g/L, and she is thrombocytopenic with a platelet count of 80 x 109/L. The white cell count is within normal limits.
You send for an urgent blood transfusion and arrange a PICU review.
The treating team is contacted by the haematologist, who has reviewed her blood film and noted the presence of target cells, Howell-Jolly bodies and sickle cells.
What is the diagnosis?
Abigail has presented in hypovolaemic shock secondary to splenic sequestration.
This is her first presentation because of sickle cell disease.
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.
Sickle cell disease 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 the 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. This causes occlusion of the microvascular circulation (vaso-occlusion). Sickled cells also undergo haemolysis – the average life span of a red blood cell drops from 120 days to only 17 days.
These changes result in a multisystem disease with the following key features:
Chronic haemolytic anaemia
Painful vaso-occlusive episodes
Multi-organ damage from micro-infarcts (including the cardiac, skeletal, splenic and central nervous system).
How is sickle cell disease inherited?
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.
Around 312 000 babies are born with sickle cell anaemia globally each year. Over 75% of them are born in sub-Saharan Africa.
Sickle cell disease is 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 sickle cell disease include sickle β thalassaemia (HbSβ0 or HbSβ+ thalassaemia) and haemoglobin SC disease (HbSC)
Individuals with sickle cell trait are benign carriers. They inherit an HbS and a normal beta-globin gene (HbAS). Sickle cell trait confers a survival advantage in malaria-endemic areas.
How is sickle cell disease diagnosed?
Universal newborn screening for sickle cell disease has been implemented in the United States and the United Kingdom but is not part of the newborn screening program in Australia.
It can be diagnosed by identifying haemoglobin variants using haemoglobin electrophoresis, high-performance liquid chromatography (HPLC) or isoelectric focusing.
What are the symptoms of sickle cell disease?
Symptom onset usually occurs within the first year of life, around five months of age. The delay in clinical signs and symptoms is due to the higher levels of HbF in infancy, preventing the polymerisation of HbS.
Patients are dealing with chronic, compensated haemolytic anaemia, a long-term condition that requires diligent care. Within this scenario, the primary causes of sudden drops in haemoglobin are splenic sequestration and aplastic crisis.
During an aplastic crisis, there is a temporary pause in the production of red blood cells, often triggered by infections, with human parvovirus B19 being the most common culprit.
Vaso-occlusive pain episodes
The cardinal feature of sickle cell disease (SCD) that dominates the condition and leads to the majority of hospital admissions is vaso-occlusion. This occurs when sickled cells block blood vessels, resulting in tissue injury and subsequent acute pain. Although the exact cause of most episodes remains unknown, several triggers have been identified, including infection, fever, acidosis, hypoxia, dehydration, and exposure to extreme temperatures.
Pain commonly manifests in various areas, such as the chest, abdomen, back, and extremities. Infants and toddlers frequently present with dactylitis, while older children tend to experience back and abdominal pain more frequently. Managing vaso-occlusive episodes necessitates early and proactive pain relief strategies to alleviate symptoms effectively.
Splenic sequestration, a critical complication of sickle cell disease (SCD), occurs when a large number of sickled red blood cells (RBCs) accumulate within the spleen. This condition can be life-threatening, as it poses a risk of hypovolaemic shock, a severe form of low blood volume.
The key characteristics of splenic sequestration include the sudden enlargement of the spleen, a significant drop in haemoglobin levels (by more than 20 g/L), thrombocytopenia (low platelet count), and an increase in reticulocytes (immature red blood cells).
Typically, this complication tends to manifest between the ages of 6 months and two years, making it a significant concern during early childhood. Prompt recognition and appropriate medical intervention are crucial in managing splenic sequestration to prevent potentially life-threatening consequences and ensure the well-being of patients with sickle cell disease.
How do we manage splenic sequestration?
Restoring the circulating blood volume often involves a blood transfusion. This approach has two primary benefits: it directly raises the haemoglobin level and encourages the spleen to release trapped red blood cells (RBCs).
However, it is essential to have a discussion with the on-call haematologist regarding transfusion targets. Excessive or rapid increases in haemoglobin levels can lead to autotransfusion, where the body starts reabsorbing its own blood cells, potentially resulting in hyperviscosity syndrome. In addition to blood transfusion, active fluid resuscitation plays a vital role in managing hypovolaemia.
Collaboration between healthcare professionals, close monitoring, and appropriate interventions are key components in the comprehensive management of splenic sequestration in individuals with sickle cell disease.
In sickle cell disease, the spleen often becomes impaired early in life due to splenic infarction, resulting in a condition known as functional hyposplenism.
Unfortunately, this diminished spleen function places patients at an elevated risk of developing invasive bacterial infections, particularly from encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitidis.
To mitigate this risk, it is crucial to promptly assess and administer empiric intravenous antibiotics to children with SCD who present with a febrile illness. This swift intervention aims to prevent the progression of potentially serious infections.
In terms of prevention strategies, two key approaches can be employed:
Firstly, prophylactic penicillin is recommended for all young children, ideally starting between the ages of 2 to 3 months. This preventive measure has proven to significantly reduce the morbidity and mortality associated with pneumococcal infections.
Secondly, adherence to the functional asplenia/hyposplenia guidelines for vaccinations is essential. Following these guidelines ensures that individuals with impaired spleen function receive the appropriate vaccinations to protect against specific pathogens.
By implementing these prevention strategies, healthcare professionals can help safeguard patients with SCD from the heightened risk of bacterial infections associated with functional hyposplenism, promoting their overall well-being and reducing potential complications.
Acute chest syndrome
The leading cause of mortality in patients with sickle cell disease is acute chest syndrome (ACS), a serious condition that requires immediate attention.
It is characterized by the presence of a new infiltrate on a chest x-ray, accompanied by respiratory symptoms such as chest pain, respiratory distress, hypoxia, cough, and/or fever.
Interestingly, the majority of ACS cases do not have a single identifiable cause. Instead, multiple factors contribute to its development, including infection, atelectasis (partial lung collapse), vaso-occlusion (blockage of blood vessels), and fat emboli resulting from infarcted bone marrow.
Effectively managing ACS involves a comprehensive approach. Treatment options include providing supplemental oxygen to improve oxygen levels, administering intravenous antibiotics to target potential infections, performing exchange transfusion to replace sickled red blood cells with healthy ones, and offering analgesia for pain relief, Physiotherapy promotes lung clearance and function, and it’s important to involve the pediatric intensive care unit (PICU) early on if there are signs of hypoxia or respiratory distress.
Before the introduction of routine screening using transcranial Doppler ultrasound (TCD), it was alarming to discover that clinically evident strokes affected up to 11% of individuals with sickle cell disease before reaching the age of 20.
In addition to these visible strokes, there is another concerning condition known as silent cerebral infarcts. These are instances where evidence of brain tissue damage due to infarction is observed through neuroimaging, despite the absence of obvious neurological symptoms. Shockingly, up to 20% of children diagnosed with sickle cell anaemia experience silent cerebral infarcts.
The implementation of regular TCD screening has proven invaluable in identifying individuals at risk of strokes and silent cerebral infarcts, enabling timely intervention to prevent long-term complications and minimize neurological damage.
Effective management strategies for individuals with sickle cell disease experiencing stroke or suspected stroke involve several key measures:
- Prompt neuroimaging is crucial to assess the extent and nature of the condition. Magnetic resonance imaging (MRI) is the preferred imaging modality due to its high sensitivity and ability to provide detailed information. However, when MRI is not readily available, a non-contrast computed tomography (CT) scan can be performed as an alternative. It is important to avoid contrast agents during imaging as they can increase the risk of hyperviscosity, a condition characterized by excessively thickened blood.
- Exchange transfusion plays a significant role in the management of strokes in sickle cell disease. This procedure involves replacing a portion of the patient’s blood with healthy donor blood, aiming to dilute the sickled red blood cells and improve blood flow to the brain. Exchange transfusion is a valuable therapeutic approach in reducing further neurological damage and promoting recovery.
Primary prevention strategies play a crucial role in reducing the risk of stroke in individuals with sickle cell disease. Here are two key approaches:
- Regular transcranial Doppler (TCD) assessments should begin from the age of 2 years. TCD is a non-invasive ultrasound technique that measures blood flow velocity in the brain’s blood vessels. By monitoring TCD velocities at regular intervals, healthcare professionals can identify children at higher risk of stroke and intervene promptly to prevent its occurrence. This proactive screening approach allows for early detection and targeted management.
- Prophylactic regular transfusions are recommended for children with persistently elevated TCD velocity. If TCD velocities indicate an increased risk of stroke, regular transfusions can be initiated as a preventive measure. These transfusions help to dilute and replace the sickled red blood cells with healthy donor blood, thereby improving blood flow and reducing the likelihood of stroke. By implementing this targeted intervention, healthcare providers can effectively reduce the risk of stroke in high-risk individuals.
Priapism, an unwanted and prolonged erection occurring without sexual stimulation, poses significant concerns for individuals with sickle cell disease.
Most episodes of priapism stem from impaired venous outflow from the penis, leading to increased pressure and the disruption of normal arterial circulation. If left untreated, episodes lasting over four hours can result in permanent tissue damage and increase the risk of erectile dysfunction, underscoring the urgency of prompt intervention.
While the optimal treatment for priapism is uncertain, there are management strategies that can help alleviate symptoms and prevent complications. These include ensuring adequate hydration, providing analgesia for pain relief, administering oxygen therapy, encouraging showering, engaging in short aerobic exercises, and promoting urination (consider catheterisation if emptying the bladder is not possible). Avoid ice, as the cold may exacerbate sickling and worsen the condition.
When priapism persists beyond the four-hour mark, it becomes a urological emergency.
- Avascular necrosis occurs at a higher rate in children with SCD.
- It commonly affects the femoral and humeral heads.
What impact does COVID have on sickle cell disease?
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.
Managing sickle cell disease in the ED?
- Vital signs
- Pallor or jaundice
- Hydration status
- Respiratory examination
- Spleen examination, with comparison to baseline
- Neurological examination
- Localising signs of infection
- 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 jaundiced or dehydrated)
- Based on assessment
- If febrile blood and urine culture
- If respiratory symptoms, consider a chest X-ray
- If neurological findings urgent neuroimaging
What is the acute management of a sickle cell crisis?
- 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.
What are the options for managing sickle cell disease long term?
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 (erythrocyte apheresis).
Hydroxyurea is a myelosuppressive agent used in the management of individuals with SCD, which has been shown to reduce vaso-occlusive complications.
A life-long cure for SCD is only available through haematopoietic stem cell transplantation.
What is the prognosis for a child with sickle cell disease?
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.
Sickle cell disease is a multisystem disease characterised by haemolytic anaemia, painful vaso-occlusive episodes and multi-organ damage from micro-infarcts.
Early diagnosis, simple prophylactic measures and parental education improve the morbidity and mortality of sickle cell disease.
Always discuss with the on-call haematologist prior to transfusing a sickle cell patient due to the risk of hyperviscosity.
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