Dr Claire Strauss & Dr Andrea Leigh

Sickle cell disease (SCD) is a condition with many life-altering consequences. Your exposure to children with SCD may depend on where you have worked, as it is primarily seen in African or Afro-Caribbean populations.  There are an estimated 14 000 people with SCD in the UK and it is routinely screened for on the Guthrie card. There are a number of emergencies children with SCD may present with, including excruciating pain. They are at risk of becoming extremely unwell very quickly so it is really important to recognise the problems these children may attend with and to understand their significance and management.

The Basics 

In SCD there is a recessively inherited point mutation of GAG to CTC on the gene for beta globin resulting in a switch of glutamate to valine. This converts ‘normal’ adult haemoglobin (HbA) to Haemoglobin S (HbS).   

Normal red cells have a smooth, elastic, biconcave shape which means that they can pass easily through small blood vessels. In SCD red HbS polymerises and as a result cells can become deformed into a sickle shape which can’t pass as easily through small vessels, causing occlusion. This prevents adequate oxygen supply to tissues causing ischaemia. Low oxygen tension promotes sickling and the cells are unable to return to their biconcave shape when oxygen tension normalises.

 Sickled red cells have a shorter life span than ordinary red cells (10-20 days instead of 90-120 days) and are destroyed at a greater rate than they are produced, resulting in chronic anaemia.

The most severe form of the disease is homozygous SCD (HbSS) although there are multiple heterozygous forms including HbSC or HbS in combination with thalassaemia. Much of the following is most relevant to HbSS or occurs to a lesser degree in those with other forms of haemoglobinopathy. A few complications may be more common in the other types.

Complications

This duo of article covers the major acute complications of SCD. Chronic and psychosocial complications, as well as those secondary to treatment, will be discussed separately. This first part addresses three of the most common problems children with SCD may encounter.

The physical consequences of SCD are primarily due to vaso-occlusive events, often triggered by stressors which increase ‘sickling’. These include infection, cold, dehydration, alcohol, physical exertion and hypoxia.

In all acute crises the child requires a full assessment and it should always be ensured that adequate analgesia and hydration are given.

Pain

This is the most common presenting complaint when children with SCD come to hospital. It can be severe and debilitating and needs to be taken seriously. Many children with sickle cell disease have unfortunately become very used to living with pain and will only present to healthcare services if they can’t manage it at home. Use a patient-reported pain scale repeatedly to assess both severity and trajectory of pain. Simple measures for pain relief (eg heat packs) are important but a sickle cell pain crisis can require significant analgesia including opioids and sometimes PCA. Escalation of analgesia should not be delayed and reduction should be guided by the child’s reported experience of pain but do remember to manage the potential side effects of opioid analgesics.

Remember that, if a child is having an episode of pain, they may also be having another form of crisis. Consider checking their haemoglobin for a fall from baseline. It is also important to ensure adequate hydration to prevent further vaso-occlusion due to dehydration. Oral hydration is ideal but children may require IV fluid supplementation.

Don’t forget to think about non-sickle cell related causes of pain e.g. abdominal pain may still be constipation or appendicitis. Bone and joint pain can be difficult to differentiate from osteomyelitis and septic arthritis. 

It is important that parents and children are familiar with how to manage pain at home e.g. avoiding precipitating factors, distraction techniques, ensuring a reliable supply of analgesia and drinking enough fluids.

Infection or sepsis

Due to functional asplenism (usually secondary to multiple splenic infarctions) or splenectomy (eg following recurrent splenic sequestration) children with SCD are more susceptible than others to infection, particularly by encapsulated organisms (Neisseria meninigitidis, Group B Streptococcus, Streptococcus pneumoniae, Klebsiella pneumonia, Escherichia coli. Haemophilus influenzae, Pseudomonas aeruginosa). They may be extremely unwell, even if this is not initially apparent. These children can also deteriorate very quickly and have a high mortality. For this reason children with SCD should come to hospital with any fever and it is essential that they receive vaccinations and take daily prophylactic penicillin V.

Upon presenting with fever children should have a blood culture and baseline bloods performed. Individual hospital guidelines may vary but have a low threshold for starting antibiotics.  Many hospitals will advise starting a broad-spectrum antibiotic, usually a cephalosporin, as quickly as possible but it is not possible to be definitive here. Tests for specific infections should be carried out as appropriate for symptoms (e.g. urine MC+S, CXR).

Osteomyelitis may be very difficult to differentiate from an acute painful crisis. Early X-Rays may not help distinguish between the two. As painful crises are more common children tend to be treated for a vaso-occlusive crisis and investigated for osteomyelitis only if symptoms are prolonged or there is another cause for suspicion. Children may be able to tell if their pain is ‘different from normal’. Common organisms causing osteomyelitis include Salmonella, Staph aureus, gram -ve bacteria. An MRI with flare is the most useful diagnostic tool. Management may vary depending on organism but, if osteomyelitis is found, it may require a prolonged course of antibiotics. The situation is very similar for a possible septic joint although ultrasound may help with the diagnosis. Aspiration may be required for confirmation of the diagnosis and washout, and antibiotic treatment implemented.

Infections may also trigger vaso-occlusive events as they increase physiological stress for the body, triggering vaso-occlusion and pain.

Acute anaemia

People with sickle cell disease will usually have a chronic anaemia with high reticulocyte count. Acute anaemia must therefore be considered in the context of a chronically low Hb so there needs to be a significant fall from baseline (usually 20g/L) or symptoms of anaemia. It is also important to avoid ‘over-transfusing’ to a level above baseline.

Differentials of acute anaemia:

1. Increased consumption
   • Haemolytic crisis
   • Sequestration
2. Reduced bone marrow production of red cells
3. Active bleeding

Increased consumption – Haemolytic or sequestration crisis

Haemolysis and splenic sequestration usually result in an increased reticulocyte count and possibly a rise in unconjugated bilirubin. They may occur in sepsis or another vaso-occlusive crisis with increased risk of haemolysis in co-existent G6PD. Consider transfusion reactions (A rare transfusion reaction is hyperhaemolysis which can occur within a week after a transfusion and is potentially worsened by further transfusions.  There is breakdown of own and donor red blood cells. Treatment is with methylprednisolone and IVIg prior to further transfusions if necessary. It classically results in increasing jaundice with ‘coca cola urine, pain and fever). 

Reduced production: 

Aplastic crisis – this is often due to parvovirus B19 although it may be due to any other cause of bone marrow failure eg. severe sepsis, drugs. It is characterised by inappropriately low reticulocytes and there may be suppression of other cell lines.

If parvovirus is suspected test for serology or PCR and ensure isolation to protect pregnant women. A child may have the classic ‘slapped cheek’ rash but not necessarily, and it can be difficult to recognise on darker skin.  Spontaneous resolution is seen with recurrence of normal haemoglobin level and reticulocyte count.

Management of any form of acute anaemia is supportive, often requiring transfusion. Rapid transfusion is required if Hb <50 g/L or if symptomatic but should not exceed >40g/L at a time as a maximum increase in haemoglobin. 

For more about sickle cell – see sickle cell part 2 (coming soon)

General References

Dick, MC and Rees DC (2019) Sickle Cell Disease in Childhood: Standards and Recommendations in Clinical Care https://www.sicklecellsociety.org/wp-content/uploads/2019/11/SCD-in-Childhood_Final-version-1.pdf

David Rees, Thomas N Williams and Mark T Gladwin (2010). Sickle-cell disease. The Lancet 376 (9757) pp. 2018-2031

University College London Hospital clinical guidelines