QuestionSBA
QuestionChoice
A knee x-ray may be helpful in showing a large effusion but the history is not suggestive of a bony injury therefore x-ray will not give you a definitive diagnosis in this case
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b
Knee x-ray
QuestionChoice
A blood film is useful in the initial diagnosis of sickle cell disease however this patient is already known to have sickle cell disease and this would not aid in the acute diagnosis
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e
Blood film assessment
QuestionChoice
This patient is septic and the most likely source is his knee. Patients with known sickle cell disease are more prone to septic arthritis and the way this is diagnosed is by aspiration of the joint in an aseptic manner and sending for culture
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a
Joint aspiration
QuestionChoice
Whilst blood cultures should always be taken in patients who present with sepsis, a positive blood culture would not necessarily tell you the focus of the infection. As the knee is the presumed focus, an aspirate directly from the joint will likely yield the definitive diagnosis
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Blood culture
QuestionChoice
Ultrasound may be used in aiding joint aspiration if the joint space is narrow or the effusion present is small, but it would not provide the diagnosis
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d
Knee ultrasound
QuestionComment
You'd definitely Sepsis 6 him before aspirating his knee though?
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QuestionComment
Definitive Ix will still be aspiration
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# Summary

Sickle cell anaemia (SCA) is an autosomal recessive condition in which a point mutation in the beta chain on chromosome 11 leads to the production of HbS (rather than HbA). HbS polymerises when deoxygenated leading to sickled red blood cells. These cells are fragile and sticky, causing vaso-occlusive crises leading to pain and ischaemia of vital organs. The most common acute presentation is painful vaso-occlusive crises, while the most dangerous is acute chest crises. Diagnosis is typically made postnatally in the UK via a national screening programme but otherwise presents with progressive anaemia in early life. Investigations may reveal microcytic anaemia with variable degrees of haemolysis, and a definitive diagnosis is achieved with haemoglobin electrophoresis +/- genetic testing. Management strategies include high-flow oxygen, IV fluids and analgesia for acute crises, hydroxycarbamide, regular exchange transfusions, vaccinations and antibiotics for chronic disease management.

# Definition

Sickle cell anaemia (SCA) is a genetic condition where normal haemoglobin (where variable HbS is present) tends to form abnormal haemoglobin molecules (HbS) upon deoxygenation leading to distortion of RBCs.

# Epidemiology

Sickle cell disease is common among individuals of Central and West African descent, where having the carrier (trait) status confers some protection against malaria. 

# Pathophysiology  

- HbS is produced when the glutamic acid at the 6th position of the β chain is replaced by valine 
- In its deoxygenated state, HbS undergoes polymerisation, forming crystals that cause polymers to form, which in turn leads to the development of RBCs with a sickle shape 
- The abnormal shape of the RBCs causes clotting in the microvasculature, which precipitates vaso-occlusive crises, leading to ischaemia of vital organs and pain
- Deformation of the RBCs leads to chronic haemolysis, which decreases the body's nitric oxide – typically needed for vasoregulation – and this leads to chronic complications such as pulmonary hypertension and leg ulcers

## Inheritance 

- Sickle cell anaemia (HbSS) is an autosomal recessive condition. The most predominant and most severe form, homozygous HbS, represents just one of the sickle cell disease syndromes.
- Other forms of sickle cell disease involve the coinheritance of HbS with other haemoglobin variants.
  - Most commonly HbC or β-thalassaemia, leading to the HbSC or HbS-βthal forms of sickle cell disease.

## Mechanism of hyposplenism

In addition, sickled red cells commonly sequester in the spleen, where they undergo phagocytosis by the reticular endothelial system, leading to extravascular haemolysis

- Initially, this leads to splenic congestion and splenomegaly
- This is followed by splenic infarction, leading to hyposplenism
- Because of splenic compromise, there is reduced immune function 
  - Individuals with sickle cell disease are prone to bacteraemia – the spleen is necessary for phagocytosis of encapsulated bacteria. This means there is vulnerability to encapsulated organisms such as Haemophilus influenzae type B.
  - Affected individuals should have up to date vaccinations for S. pneumoniae, H. influenzae B and N. meningitidis.


# Signs and Symptoms

## Vaso-occlusive crises

Painful vaso-occlusive crises are the most common acute presentation of sickle cell anaemia

- Primarily caused by microvascular obstruction due to RBC sickling and inflammation
- May be triggered by local hypoxia (eg. in cold weather)

## Acute chest crisis

Acute chest crises are the most dangerous acute presentation

- 3% mortality rate, causing 25% of sickle cell-related deaths 
- The cause is often unknown (maybe infectious)
- Patients present with tachypnoea, wheeze, and cough, with hypoxia and pulmonary infiltrates on chest X-ray

## Other complications 

- Splenic infarction and subsequent immunocompromise
- Sequestration crisis
- Osteomyelitis
- Stroke
- Dactylitis
- Poor growth
- Chronic renal disease
- Gallstones
- Retinal disorders
- Priapism
- Pulmonary fibrosis and pulmonary hypertension
- Iron overload from repeated blood transfusions
- Red cell aplasia (due to parvovirus B19 infection in the presence of chronic haemolytic anaemia)

**Clinical severity** is highly variable: some patients have few symptoms; others have severe and frequent crises, haemolytic anaemia and end-organ damage

- This is due to a range of factors such as the amount of HbF (foetal haemoglobin) – higher levels of HbF reduce the severity of clinical complications
- Patients with Hb SC disease have milder anaemia and suffer fewer crises than people with Hb SS disease 
- Patients with Hb SC disease are however more prone to sickle cell retinopathy 
  - Ophthalmological review is needed annually for all patients with Hb SC disease

# Investigations

- Bedside - peak flow, which is essential for monitoring patients with chest crisis
- **FBC** may show microcytic anaemia with variable degrees of haemolysis 
  - Reticulocytosis and unconjugated hyperbilirubinemia may be noted

- Typical **blood film** findings include: 
  - characteristic sickle cells
  - target cells
  - reticulocytosis with polychromasia 
  - features of functional hyposplenism (Howell–Jolly bodies, nucleated red cells)

Definitive diagnosis is with **haemoglobin electrophoresis** +/– genetic testing. However, many labs use high-performance liquid chromatography (HPLC) and/or isoelectric focusing (IEF) instead of HB electrophoresis. 

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## Screening for sickle cell disease

- Sickle cell disease in the UK is typically diagnosed postnatally (by the national screening programme)
- Additionally, all patients of African or Caribbean descent should have a sickle cell test prior to surgery 
- Otherwise, it can present with progressive anaemia in early life when levels of foetal haemoglobin (which contains γ-chains) fall and are replaced by HbS (containing the variant β-globin)

# Management 

## Acute sickle cell crisis

Treatments include: 

- High-flow oxygen 
- IV fluids and analgesia
- Top-up transfusions – required in some severe cases

Note: ABO-compatible red cells matched for Rhesus and Kell antigens should be given as this will inhibit the development of antibodies that can otherwise complicate future transfusions.


## Chronic sickle cell disease

* **Hydroxycarbamide** if frequent crises occur
  * Increases foetal haemoglobin concentrations – needs to be balanced with risks of marrow suppression, reduced fertility and risk of teratogenicity

* Alternatively regular exchange transfusions may be required for frequent sickle cell crises, acute chest syndrome, priapism and stroke prevention 
* **Vaccinations** and **antibiotic prophylaxis** – in view of hyposplenism and subsequent immunocompromise
* Newer therapies include: 
  * crizaniluzumab (p-selectin inhibitor) for treatment of pain crises 
  * voxelotor (haemoglobin oxygen-affinity modulator) for haemolytic complications

* Bone marrow transplant and gene-editing techniques are now becoming possible curative options for some patients

# NICE Guidelines

[Click here to see information on NICE CKS on sickle cell](https://cks.nice.org.uk/topics/sickle-cell-disease/)
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Joint aspiration is crucial in patients with sickle cell disease who are at increased risk of septic arthritis, as it helps confirm the diagnosis, identify the causative organism, and guide targeted treatment.
A 27 year old male with known sickle cell disease presents to his local accident and emergency department with an eight hour history of a painful right knee. His triage observations are as follows: SpO<sub>2</sub> 97% on air, respiratory rate 18, pulse 108 (regular), blood pressure 90/60 mmHg, temperature 39.2°C.

His knee is erythematous and hot to the touch and he has very minimal active movement.

What test will give you the definitive diagnosis?
a