Sickle Cell Disease Module

It is very important to know whether our patient has sickle cell or not since this would make them a high-risk patient that needs specific acute (and chronic) management. Clinicians should think about the possibility of SCD given the ethnicity (Sub-Saharan Africa) and the presenting symptoms suggestive of dactylitis. Furthermore, the patient was born outside the UK, therefore he missed the routine newborn screening process.

Newborn screening is the best way to identify children with SCA but this can be quite challenging in Sub-Saharan Africa for logistical reasons. The majority of low-income countries lack systematic newborn screening.

Studies have been conducted to create algorithms to identify those who need to be tested for sickle cells. The Kilifi algorithm includes five clinical situations that are common sickle cell presentations – clinical jaundice, severe anaemia, bone and joint infections, and stroke.

Newborn screening: sickle cell screening is donethrough heel-prick blood at five days of life. It has been routine practice in the UK since 2006.

Newborn screening improves the care and health of sickle cell patients by:

• referring patients early to specialist clinics
• providing early antibiotic prophylaxis
• providing adequate immunisations to prevent severe bacterial infections
• monitoring for acute and chronic complications and being able to start medications early to prevent complications.

Blood film: Some sickle cell patients may have not had any screening if they were not born in the UK. Clinical suspicion based on ethnicity should prompt adequate investigations to yield the diagnosis. Sickle cells can be seen in the blood filmfrom the first year of life. Other associated signs can be anaemia and high reticulocyte count.

Haemoglobin electrophoresis: To reach a definitive diagnosis, Hb electrophoresis is used. This is a laboratory technique to separate normal haemoglobin from abnormal haemoglobin. Be careful if the patient has received a recent blood transfusion since it may be misinterpreted as sickle cell trait instead of sickle cell disease. In these cases, repeat the Hb electrophoresis three months after the last blood transfusion.

Afro-Caribbean patients should be screened for sickle cell before anaesthesia for possible pre-operative transfusion.

The patient was diagnosed with Salmonella osteomyelitis. Overall, Staphylococcus aureus is the most common causative agent of osteomyelitis in children. However, the ratio of Salmonella to S. aureus for osteomyelitis in the sickle cell population is higher (2.2:1).

When a patient is diagnosed with Salmonella osteomyelitis, investigations for sickle cell disease should be carried out. The reason why Salmonella osteomyelitis is so common in sickle cell patients is still unclear but probably the Salmonella bacteria enters the blood-stream via micro-infarction of the gut as a result of impaired intestinal microcirculation. Infarcted areas of bone tissue can be infected with Salmonella resulting in osteomyelitis.

The other possible differential diagnosis in this case could be dactylitis due to vaso-occlusive episodes resulting in an acute painful crisis. Vaso-occlusion happens when the sickled red cells limit the microcirculation of various organs. Bones are the most common place for vaso-occlusion because the bone marrow is hypercellular and susceptible to reduced blood flow and regional hypoxia resulting in infarction.

Clinically, vaso-occlusive episodes present with localised swelling, tenderness and erythema of a region. In older children, long bones are more affected while in younger children small bones of the hands and feet are affected.

Dactylitis is far more common than osteomyelitis. However, these two entities are difficult to discern clinically and can coexist.

TIMELINE OF CLINICAL SYMPTOMS IN SICKLE CELL DISEASE:

Sickle cell patients are more susceptible to severe bloodstream bacterial infections due to lack of opsonisation by antibodies or complement to remove circulating bacteria. This phenomenon is called functional asplenia.

In patients with sickle cell anaemia, functional asplenia develops at 1 year of age. After 6-8 years, anatomical asplenia occurs due to repeated spleen infarctions. Later on, some sickle cell patients would need a splenectomy so they would become surgically asplenic. Surgical asplenia is even more severe than functional asplenia.

Mortality among patients with asplenia is commonly caused by Streptococcal pneumonia. Patients with asplenia are at risk of infections by encapsulated organisms: Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis and other bacteria such E. coli and Staphylococcus aureus. Symptoms may be non-specific in the beginning with patients quickly developing septic shock and disseminated intravascular coagulation.

1. Education: parents and patients should understand the lifelong risks they face, the importance of vaccination and compliance with antibiotic prophylaxis and the need for urgent action during a febrile episode. GPs and local hospitals should provide easy access to medication and vaccinations to ensure good compliance.
   
   
2. Vaccination: PCV13 (pneumococcal vaccination), meningococcal vaccines, and Hib conjugated vaccines are important to prevent life-threatening sepsis. Sickle cells patients should receive the above vaccines as per the UK calendar schedule. If the patient comes from a different country and has not received vaccinations, please refer here to catch up. 
   
   Sickle cell patients also qualify to receive the annual influenza vaccine, since influenza virus infection predisposes to bacterial pneumonia and sepsis caused by S. pneumoniae and S. Aureus.
   
   
3. Prophylactic antibiotic therapy: lifelong oral penicillin prophylaxis is recommended to all sickle cell patients since it has dramatically reduced mortality from pneumococcal sepsis in younger children. In older children, studies have not demonstrated a significant reduction of the incidence of invasive pneumococcal infection. This could also be due to the fact that pneumococcal infection rates in the community decrease significantly after 5 years of age. It must be noted, however, that these studies were completed before the universal use of pneumococcal vaccine in infants, and before the increased prevalence of colonization and infections with penicillin resistant pneumococci.
   
   
   Start penicillin prophylaxis by 90 days of life and continue for life.

If the patient has a penicillin allergy, erythromycin is a good alternative.

If the patient travels to malaria areas, provide malaria prophylaxis.

4. Early empirical antimicrobial therapy during febrile episodes.

Fever in an asplenic patient should be managed promptly since it could be the initial signs of a fatal disease. The patient should be educated to seek medical help when fever develops to receive early antimicrobial treatment (ceftriaxone) and further support.

Pain due to vaso-occlusive crisis (VOC) is a very common presentation in sickle cell patients. Common sites of pain are bones (long bones, dactylitis) or abdominal pain. Painful crises are due to vaso-occlusion by sickled red cells generating an ischaemic tissue injury from blood flow obstruction. On average, a painful crisis may last for 4-5 days.

Studies have shown that pain is usually undertreated, as sickle cell patients may not look uncomfortable since they have learned to adapt to a lifetime of chronic pain with several non-pharmacologic therapies (distraction techniques, hypnosis, cognitive-behavioural therapy). This child’s pain should be evaluated with an appropriate pain scale for his age. Furthermore, if the patient or his parents report severe pain, this should be taken seriously and acted upon.

The majority of painful crises are not severe and can be managed at home. Frequent crisis and chronic pain can negatively impact the child’s development and personal growth, so effective treatment is crucial. Children should identify and avoid pain triggers. Infections, fever, acidosis, hypoxia, dehydration and exposure to extreme temperatures can trigger VOC even though often no cause is identified.

Pain can not only be managed with drugs but also with psychological coping strategies such as distraction techniques or other therapies (i.e. massage, watching TV).

Home analgesia:

• Advise families at home to increase fluid intake to avoid dehydration (dehydration will prolong painful episodes).

• Alternating paracetamol and ibuprofen is the analgesic regimen of choice in mild-to-moderate pain. Avoid long courses of NSAID treatment (>72 hours) due to the potential renal side effects of sickle cell patients who are at increased risk of chronic renal failure.

• For severe pain: a weak opiate can be added. Dihydrocodeine can be used in under 13 years of age and codeine after this age. Of note, at least 20% of children will not respond to codeine because they lack the enzyme needed to convert it to morphine.

If the patient is still in pain after using this regimen, they should be assessed in hospital. Children should not be treated with morphine at home except in exceptional circumstances and always guided by individualised care plans.

When sickle cell patients present to ED, they have usually already used their home pain medications and pain is still not under control.  Therefore, aggressive analgesia should be given with the next step in the pain treatment ladder, which is strong opiates (morphine, oxycodone, hydromorphone or fentanyl). Some clinicians are scared of using opioids due to concerns that they may cause acute chest syndrome. Opioids do not cause ACS but they can exacerbate hypoxia in patients with ACS. A cautious but rational use of opioids in combination with adequate monitoring is effective and safe to treat painful crises.

Morphine sulphate is the commonest strong opioid to start with. Offer a bolus of strong analgesia within 30 minutes of arrival to hospital to all patients with severe pain and with moderate pain who have already had some analgesia before presentation.

The IV route is used for rapid effect since the PO morphine requires titration and may take some time to act. If IV route is not available, the subcutaneous route is also reliable. Alternatives to morphine are hydromorphone or fentanyl. They should be used for patients who cannot tolerate morphine side effects (extreme pruritus or nausea).

Do not use pethidine since it can cause seizures and CNS hyperexcitability.

Initiate a continuous infusion (patient controlled analgesia) if repeated bolus doses of a strong opioid are needed within 2 hours.

In addition to opiates, continue to offer paracetamol and NSAIDS (unless contraindicated). Offer antiemetics, laxatives, and antihistamines to minimise morphine side effects (pruritus, nausea and constipation). Monitor vital signs for respiratory depression. Naloxone (opioid antidote) should be available in ED in case of severe respiratory depression.

A newer therapy option is ketamine. Recent studies have shown that low-dose ketamine can reduce pain in acute painful crises of sickle cell patients as well as being an opioid-sparing drug.

During a painful crisis, clinicians should also be vigilant of other concurrent problems.

Priapism is a sustained, painful and unwanted erection. Priapism is more common in teenagers which makes it complex since they’re usually shy and reluctant to seek medical help. When it occurs in a pre-pubertal boy, it has a better prognosis for normal erectile function than in post-pubertal boys.

A prolonged attack (>3 hours) should be treated as a surgical emergency.  If untreated, it may result in cavernosal fibrosis and subsequent impotence. In addition, blood transfusion may be indicated as part of the overall management plan if a shunt needs to be performed.

Other non-pharmacological treatments are bladder emptying, exercise such as jogging, warm baths and analgesia.

https://radiopaedia.org/articles/sickle-cell-disease-acute-chest-syndrome-1?lang=gb

Acute chest syndrome is an acute inflammatory lung injury that usually follows vaso-occlusive crisis. It is defined by the presence of a new pulmonary infiltrate on a chest XR in association with fever and respiratory symptoms (cough, chest pain, desaturations and wheezing). It is the most prominent cause of mortality in children with SCD and it is the second most common cause for hospitalisation in these patients.

The most common findings on CXR are segmental atelectasis/consolidation  in the lower lobe, and/or pleural effusion. Other sickle cell disease sequelae can be seen such as bone infarcts, rib enlargement and cardiomegaly from anaemia.   Young children present with a mild disease simulating a community-acquired pneumonia (bacterial or viral). Older children and adults usually present with ACS 2-3 days after hospitalisation due to pulmonary infarction (in situ sickling), hypoventilation due to rib infarction (which may be exacerbated by recent narcotic administration) or fat embolism.

Haemoglobin is usually lower than baseline and white cells count is often raised.

The treatment for ACS is mainly supportive: 

• Oxygen: supplemental oxygen should be given only when the patient is hypoxic (saturation of oxygen < 94%). As a side effect, oxygen can suppress bone marrow and increase transfusion needs.
• Incentive spirometry or chest physiotherapy: prevent atelectasis in the wakeful child with incentive spirometry. If the patient is not able to comply with incentive spirometry due to age or extreme thoracic wall pain, then request chest physiotherapy with positive expiratory pressure. Incentive spirometry has also demonstrated to improve outcomes in SCD without respiratory symptoms and with back pain.

• Mechanical or non-invasive ventilation: children with ACS may require ventilatory support. They should be admitted to hospital in case of clinical deterioration to receive ICU treatment.

• Fluid therapy: fluids should be given carefully. Prescribe 75% of daily maintenance fluid of normal saline or 5% dextrose and normal saline. Avoid fluid boluses unless the patient is very hypovolemic (sepsis, vomiting illness).

Overhydration can:

– produce atelectasism, worsening acute chest crisis

– result in hyperchloremic metabolic acidosis which may promote sickling

– result in pulmonary oedema (especially if there is a concurrent use of opiates for pain control which increases vascular leak).

• Antimicrobials: Sickle cell patients with ACS should receive antibiotics since they are key to decreasing inflammation. Pulmonary infections have a crucial role in the pathology of acute chest syndrome: bacteria and viruses can infect the lung creating an excessive inflammatory response due to systemic endothelial dysfunction triggering ACS. The regimen should include a macrolide and third generation cephalosporin in order to cover Chlamydia pneumoniae, Mycoplasma pneumoniae, Streptococcus pneumoniae and Staphylococcus aureus. Antibiotic therapy should be reviewed once blood culture results are available. Tamiflu can be considered if results are positive for influenza.

• Bronchodilators: asthma and bronchospasm can contribute to ACS as a risk factor. Therefore, inhaled bronchodilators are advised even though the evidence of efficacy remains weak according to a recent Cochrane review.
• Corticosteroids:  there is a lot of controversy on steroidal treatment. A low dose steroid has demonstrated to improve morbidity and to reduce the need for blood transfusion. However, there are documented adverse events such as haemorrhagic cerebrovascular accidents or recurrence of VOC after drug withdrawal, which represent a drawback in its regular use.
• Anticoagulants: tinzaparin (low-molecular-weight heparin) has been shown to reduce the duration and severity of VOC pain by ameliorating vaso-occlusion however is not used systematically in ACS.
• Inhaled NO: SCD patients have reduced nitric oxide due to a chronic inflammatory state that worsens the ACS. Many clinicians have studied the role of NO in SCD but, unfortunately, studies have not shown a significant difference in symptom improvement and resolution of ACS episodes in patients with inhaled NO therapy vs placebo.

Top-up transfusion should be considered giving the acute presentation and the severe anaemia. Before any transfusion, discuss the case with the local haematologist. There are 2 types of blood transfusions that may be indicated in sickle cells patients:

“Top-up” transfusion:

Top-up transfusions aim to improve oxygen delivery, to restore Hb to a normal steady state (target Hb should be less than 10 g/dl or haematocrit 0.35 to avoid increased blood viscosity.

Blood volume for top-up:

[Desired Hb – Actual Hb] X Weight (kg) x 3 = volume of packed red cells.

Rate of 5ml/kg/hour. Furosemide is not required as it increases blood viscosity.

Exchange transfusion:

Aim to reduce HbS % <30% with a target Hb less than 11.5 g/dl or haematocrit less 0.35 by performing a total exchange of 1-2 times the calculated blood volume. It can be performed by either manual or automated exchange. Usually, children would have had a top-up already but the haemoglobin would still be low. This treatment is usually done in the ICU setting.

Oral hydroxycarbamide (previously called hydroxyurea) increases foetal haemoglobin production and therefore, it decreases sickled haemoglobin. It also improves red cell hydration, decreases the neutrophil count and modifies red cell–endothelial cell interactions. Hydroxycarbamide is indicated in sickle cell patients because it decreases the incidence of pain episodes, acute chest crises and the number of transfusions required.

Hydroxycarbamide should be offered to all children with HbSS/Sβ0 thalassaemia aged 9–42 months regardless of the clinical severity of their illness.

It should also be offered to patients with severe complications (if they are not already taking it):

– 3 or more episodes of acute vaso-occlusive painful episodes each year

– Recurrent or severe Acute Chest Syndrome

5-10% of children with SCA will have a stroke during their lifetime. Peak age is between 2-10 years. Furthermore, ¾ of children with a positive past medical history of stroke will go on to have another or several more strokes since acute neurological ischaemia is more likely to occur in children with pre-existing cerebrovascular lesions during acute anaemic events or with other acute complications.

Proximal vessel stenosis predisposes children to acute cerebral infarction. Occasionally older children present with subarachnoid or intracerebral bleeds, which may be related to single or multiple cerebral artery aneurysms.

Children can experience intellectual impairment, increased frontal lobe-related attention problems, impaired executive functioning and behavioural issues due to cerebro-vascular disease. 

About 20% of children with SCD will have a silent cerebral infarct on MRI that are not associated with an overt neurological episode. They’re associated with mild cognitive impairment and may be discovered with a neurocognitive test.

Acute management:

• Urgent imaging with CT scan and/or MRI/MRA to define the event and exclude a haemorrhagic component.
• If neuroimaging shows intracerebral or subarachnoid haemorrhage, refer urgently to the neurosurgical team.
• Exchange transfusion to reduce the risk of progression of the lesion.

For specific diagnosis and treatment of acute stroke, read the RCPCH Stroke guidelines: https://www.rcpch.ac.uk/sites/default/files/2019-04/20160203%20Key%20Recommendations%2008.04.19.pdf

In children, cerebral ischaemic damage is often due to stenotic lesions in the internal carotid artery (ICA), middle cerebral artery (MCA) or anterior cerebral artery (ACA). The high blood flow velocities through these stenotic segments can be detected using transcranial doppler ultrasound (TCD). Annual screening with TCD is recommended to all SCD patients > 2 years old.

Patients with a time-averaged mean velocity in the ICA/MCA/ACA segments >200cm/sec are at high risk for stroke. Patients in the high-risk group can receive regular blood transfusions in order to reduce the risk of having a stroke. A clinical trial on children with abnormal TCD and already on regular blood transfusions showed that switching to hydroxycarbamide was equivalent to transfusion for primary prevention of stroke.

Patients with conditional velocities (170-200cm/sec) are at moderate risk and should be closely monitored.

Chronic transfusions can reduce the risk of recurrent stroke from 50-70% to 13% (secondary stroke prevention). Hydroxycarbamide is less effective at secondary stroke prevention so it is used only when transfusions are contraindicated.

The aim of the transfusion is to maintain HbS level < 30%. Top-up transfusions should be done every 3-4 weeks and continued throughout childhood. Children on regular transfusion should be vaccinated against hepatitis B (if they are not immune already).

A common long-term side effect of transfusion therapy is iron overload, therefore iron chelation should be started in the following scenarios:

– after 1 year of transfusions

– serum ferritin> 1000 ng/mL on 2 readings 4 weeks apart

– evidence of iron load in the liver through MRI.

Prevention for silent strokes:

The option of chronic transfusion should be discussed with parents. Regular transfusions decrease the number of further neurological events even in silent infarcts. There is no evidence on how to screen children for silent cerebral infarcts but there should be a low threshold for MRI when there are cognitive concerns including poor school performance.

Acute splenic sequestration presents with an acute fall of Hb (more than 2 g/dl below the steady-state of Hb), an elevated reticulocyte count and splenomegaly. It is a serious complication with high mortality if not recognized. 

Prompt intervention with transfusion can be life-saving.  Children with recurrent splenic sequestration should be considered for splenectomy.

Differential diagnosis:

Transient red cell aplasia: usually due to Parvovirus B19 infection. The haemoglobin drop is over a period of a week with very low reticulocytes. It may be associated with fever, headache and abdominal pain. IgM for Parvovirus is usually positive. It takes about 7 days for the reticulocytes to recover and top-up transfusion is often needed.

Malaria: the patient was in Nigeria for 2 months and has not been compliant with treatment. Unlike sickle cell carriers, sickle cell patients are at higher risk of contracting malaria and suffering from severe disease. Malaria can present with pallor and jaundice. Thick and thin films should be ordered to look for parasites.

Which of the following statements is FALSE concerning Sickle Cell Anaemia?

A. It is a recessive autosomal inherited blood disorder

B. The sickle shape of the cell is due to an abnormality in haemoglobin

C. Symptoms are never seen in children

D. Fatigue is a common symptom

The correct answer is C.

Symptoms are never seen in children.

Clinical presentation usually begins after the first year of life, when foetal haemoglobin (HbF) decreases in favour of HbA. Patients with SCA (HbSS) usually become symptomatic at this point when HbF decreases and HbSS increases.

Why is sickle cell disease more common near the equator (Africa, Caribbean countries)?

A. Sickle cell trait is a genetic mutation that provides protection against malaria

B. Sickle cell disease is a genetic mutation that provides protection against malaria

C. Sickle cell disease is a genetic mutation that provides protection against trypanosomiasis

D. Sickle cell trait is a genetic mutation that provides protection against trypanosomiasis

The correct answer is A.

Sickle cell trait is a genetic mutation that provides protection against malaria.

Sickle cell trait provides protection against malaria while sickle cell disease confers high risk for malaria parasite infection.

What infections are sickle cell patients more at risk of?

A. Pneumococcal sepsis

B. Rotavirus gastroenteritis and dehydration

C. Recurrent UTIs

D. Mycoplasma pneumonia

The correct answer is A.

Pneumococcal sepsis.

Sickle cell patients have functional asplenia and they are at high risk for encapsulated bacterial infections, especially Streptoccocus pneumoniae.

Transfusions in sickle cell patients are indicated in patients with:

A. Any surgical procedures

B. Acute fulminant priapism unresponsive to treatment

C. Asymptomatic functional asplenia

D. Moderate acute chest syndrome without hypoxia

The correct answer is B.

Acute fulminant priapism unresponsive to treatment.

Blood transfusions are indicated in major surgical procedures, acute priapism > 3 hours not responsive to treatment, severe acute chest syndrome with hypoxia requiring ICU.

What are specific treatments for sickle cell disease?

A. Regular blood transfusions

B. Hydroxycarbamide

C. Bone marrow transplant

D. All of the above

The correct answer is D.

All of the above.

Specific treatments for sickle cell disease are regular blood transfusions and hydroxycarbamide. Bone marrow transplant is a curative treatment for sickle cell patient but it is a high-risk therapy and only used in selected patients.

In an outpatient sickle cell visit, what would you be a priority to assess?

A. Haemoglobin A1C level

B. Saturation of oxygen

C. Reflexes

D. Vaccination history

The correct answer is D.

Vaccination history.

Vaccination history is key to prevent infective complications: sickle cell patients should receive all the scheduled vaccinations including pneumococcal vaccine in addition to annual flu vaccine and meningococcal vaccination.