Sickle cell disease


– Homozygous sickle cell disease (SCD) is a life-threatening genetic disorder of haemoglobin (Hb). The abnormal Hb (HbS) results in the distortion of red blood cells into a sickle shape leading to increased destruction (haemolysis), an increase in blood viscosity and obstruction of capillaries (vaso-occlusion).
– SCD is common in sub-Saharan Africa (1 to 3% of births), on the American continent, in India and in the Mediterranean basin.

Clinical features

– Symptoms generally begin after 6 months of age.
– Major signs: recurrent painful crises, chronic anaemia, splenomegaly and frequently, growth retardation and malnutrition in children.
– Serious acute life threatening complications such as stroke, overwhelming infections and acute chest syndrome.
– In populations in whom the disease is frequent, diagnosis is suggested by a family history of similar clinical signs.

Major acute manifestations

Painful vaso-occlusive crises (VOC)

– Children under 2 years present with the hand-foot syndrome or dactylitis (acute pain and swelling in the hands or feet).
– Children older than 2 years and adults present with acute pain affecting the back, chest, abdomen (can resemble an acute abdomen) and extremities.
– Young children may have non-specific signs of a VOC: refusal to walk, irritability, lack of appetite, crying, whimpering or moaning when touched, etc.
– Look for an associated infection that might have precipitated the VOC.
– In case of bony pain in a single location, unresponsive to analgesics (or a persistent limp in a child) associated with fever and erythema or swelling, consider an osteomyelitis.

Fever

Look for infection: in particular pneumonia, cellulitis, meningitis, osteomyelitis and sepsis (patients are particularly susceptible to infections especially due to pneumococcus, meningococcus and Haemophilus influenzae); malaria.

Acute severe anaemia

– The chronic anaemia is often complicated by acute severe anaemia with gradually appearing fatigue, pallor of the conjunctivae and palms, shortness of breath, tachycardia, syncope or heart failure.
– The acute anaemia can be due to:
• Acute severe haemolysis often secondary to malaria: fever, haemoglobinuria (dark urine) and yellow conjunctivae.
• Splenic sequestration (trapping of blood cells in the spleen), mostly in children 1 to 4 years: sudden enlargement of the spleen, severe left upper quadrant pain, thrombocytopenia. Can lead to shock.
• Aplastic crisis (transient suspension of red blood cell production by the bone marrow): impalpable spleen and absence of reticulocytes.

Stroke

– Most often ischaemic (due to vaso-occlusion in cerebral vessels) but a stroke can also be haemorrhagic.
– Sudden loss of motor function or aphasia, in children and in adults.
– Signs can resemble meningitis and cerebral malaria: headache, photophobia, vomiting, stiff neck, alteration of consciousness and neurologic signs or rarely seizures.

Acute chest syndrome (ACS)

– Chest pain, tachypnoea, respiratory distress, hypoxia; fever (more frequent in children); pulmonary infiltrate on chest x-ray. Often proceeded by a VOC.
– Complications: multiorgan failure (lung, liver, kidney).

Priapism

Painful prolonged erection in the absence of sexual stimulation, also occurring in young boys. Risk of necrosis and irreversible erectile dysfunction.

Laboratory and other examinations

Diagnosis

– Hb electrophoresis confirms the diagnosis but is often unavailable.
– If not available, a positive Emmel test (or sickling test) in the presence of clinical signs of sickle cell disease supports the diagnosis.

Other examinations

Tests

Indications

Haemoglobin

• At the time of diagnosis and annually (frequently 7 to 9 g/dl).
• In case of VOC, fever, acute anaemia (≤ 5 g/dl or drop in Hb ≥ 2 g/dl below the patient’s baseline), stroke, ACS.
• For monitoring of transfused patients.

Platelets

• At the time of diagnosis and annually.
In case of acute anaemia (thrombocytopenia - platelet count 100 000/mm3 if splenic sequestration).

Urine dipstick

• In case of fever: look for a urinary tract infection.
• In case of acute severe anaemia: look for haemoglobinuria.

Malaria test

In case of VOC, fever, acute anaemia or stroke.

Lumbar puncture

In case of fever with meningeal signs or unexplained coma.

Other
(if available)

• Complete blood count and reticulocyte count.
• Blood culture in case of fever.
• X-Ray if suspicion of pneumonia, osteomyelitis, ACS.

Management of major acute manifestations

Painful vaso-occlusive crisis (VOC)

– Moderate pain (at home):
• Generous oral hydration (water, soup, juice, coconut water): minimum 100 ml/kg daily in children and 50 ml/kg daily in adults (2.5 to 3 litres/ daily);
• Warm compresses (application of cold is contra-indicated);
• Level 1 (paracetamol and ibuprofen) and level 2 (tramadol) analgesics;
• If pain is not controlled at home within 24 hours, seek medical attention.

– Severe pain or pain not controlled at home (in hospital):
• IV hydration (Appendix 1b) and PO; monitor for fluid overload, discontinue IV fluids progressively after 24 to 48 hours;
• Level 3 analgesics (morphine);
• Do not give routine antibiotics in the absence of fever; do not transfuse for VOC.

For the treatment of pain according to intensity, see Pain (Chapter 1).

Fever and infection

– Admit to hospital:
• All children less than 2 years;
• Children with fever ≥ 38.5 °C and adults with fever ≥ 39.5 °C; patients who are critically ill appearing1 or have acute anaemia.

– PO or IV hydration (Appendix 1a).

– Treat malaria if present.

– Treat bacterial infections according to cause.

– Treat all patients with respiratory symptoms for pneumonia and ACS.

– In case of osteomyelitis:
ceftriaxone slow IV2 injection (3 minutes) or IV infusion (30 minutes)
Children < 40 kg: 50 mg/kg every 12 hours
Children ≥ 40 kg and adults: 2 g every 12 hours
cloxacillin IV infusion (60 minutes)3
Children < 40 kg: 50 mg/kg every 6 hours 
Children ≥ 40 kg and adults: 3 g every 6 hours 
Administer IV therapy for at least 14 days. Then if the patient has improved, change to the oral route for an additional 14 days of treatment with a combination of:
ciprofloxacin PO
Children < 35 kg: 15 mg/kg 2 times daily
Children ≥ 35 kg and adults: 500 mg 2 times daily
amoxicillin/clavulanic acid PO (see below) 

– If the source of infection is unknown:
ceftriaxone IM or slow IV2  injection (3 minutes) or IV infusion (30 minutes)
Children < 20 kg: 50 mg/kg once daily (max. 2 g/day)
Children ≥ 20 kg and adults: 1 to 2 g once daily

After 48 hours re-evaluate the patient:
• If the patient is improving (afebrile, can drink), change to:
amoxicillin/clavulanic acid (co-amoxiclav) PO for 7 to 10 days. Use formulations in a ratio of 8:1 or 7:1 exclusively. The dose is expressed in amoxicillin:
Children < 40 kg: 50 mg/kg 2 times daily 
Children ≥ 40 kg and adults:
Ratio 8:1: 3000 mg daily: 2 tab of 500/62.5 mg 3 times daily
Ratio 7:1: 2625 mg daily: 1 tab of 875/125 mg 3 times daily

Patients over 2 years without acute anaemia can continue treatment as outpatients.
Patients under 2 years or with acute anaemia or who cannot be monitored and treated at home by their family should complete PO antibiotherapy in hospital.
• If the patient is not improving, continue ceftriaxone until the patient is afebrile, then, change to PO treatment. Monitor for acute anaemia.

Acute severe haemolysis

(in hospital)
– Treat malaria if present.
– Transfuse packed red blood cells4 5 if Hb < 5 g/dl or drop of 2 g/dl below the patient’s baseline. Target a Hb level of 9 g/dl.
• Start with 10 to 15 ml/kg in 3 to 4 hours. For information, 10 ml/kg of packed red blood cells usually raise the Hb by 2.5 g/dl.
• Repeat the Hb. If a second transfusion is needed, check for signs of fluid overload before starting the transfusion.
• Measure Hb and perform urine dipstick in the following days. Further transfusions may be necessary if haemolysis is ongoing.

Aplastic crisis

(in hospital)
– Treat an associated bacterial infection if present.
– Transfuse as for haemolysis. Repeat the Hb every other day. An increasing reticulocyte countand a gradual increase of the Hb indicate improvement. Follow patient until they have reached their baseline Hb.

Splenic sequestration

(in hospital)
– Treat hypovolaemic shock if present.
– Monitor the size of the spleen.
– Transfuse if Hb < 5 g/dl, target a Hb level of 7 to 8 g/dl maximum.
– Administer ceftriaxone as above.
– After clinical improvement, monitor for relapse (follow the size of the spleen).
Note: splenectomy is contra-indicated (high operative mortality).

Stroke

(in hospital)
– The treatment of choice for ischaemic stroke is an exchange transfusion to lower the concentration of HbS. Transfer the patient to a specialized facility for further management (including prophylactic therapy to prevent recurrences with transfusion program, hydroxyurea).
– If the patient is awaiting transfer or if transfer is not possible:
• Oxygen continuously, at least 5 litres/minute or to maintain the SpO2 between 94 and 98%.
• Treat seizures if present.
• Transfuse if the Hb ≤ 9 g/dl. Target Hb of 10 g/dl.
• After the transfusion provide IV hydration (Appendix 1a).

Acute chest syndrome

(in hospital)
– Measure SpO2 and administer oxygen as in stroke.
– IV hydration (Appendix 1a) while monitoring for fluid overload.
– Antibiotics:
ceftriaxone slow IV2 injection (3 minutes) or IV infusion (30 minutes) for 7 to 10 days
Children < 20 kg: 50 mg/kg once daily (max. 2 g daily)
Children ≥ 20 kg and adults: 1 to 2 g once daily
azithromycin PO for 5 days
Children: 10 mg/kg once daily (max. 500 mg daily)
Adults: 500 mg on D1 then 250 mg once daily from D2 to D5

– Transfuse if symptoms are unresponsive to antibiotics and Hb < 9 g/dl.
– If wheezing is present treat with:
salbutamol aerosol (100 micrograms/puff)
Children and adults: 2 to 4 puffs with a spacer every 10 to 30 minutes as needed
– Encourage deep breathing (incentive spirometry hourly).
– Treat pain (see Pain, Chapter 1).

Priapism

– PO and IV hydration (Appendix 1b), encourage urination, apply warm compresses, treat pain.
– Erection > 4 hours: consider transfusion and refer to surgery.

Prevention of complications

Certain complications can be avoided with appropriate health education of patients/families, routine preventive care and regular follow-up.

Education of patients (including children) and families

Basic knowledge

  • Disease
  • Treatment
  • Monitoring
Chronic, necessarily transmitted by both parents, non-contagious.
Routine (next page) and symptomatic (pain).
Size of the spleen, temperature, baseline Hb.

Major precipitating factors of a painful crisis and how to prevent them

  • Cold
  • Excessive heat
  • Tight clothing
  • Dehydration
  • Excessive effort
  • Infections
Wear warm clothing, avoid bathing in cold water.
For example, avoid going out at mid-day.
Wear wide comfortable clothing without elastics.
Drink plenty of fluids.
Moderate physical activity is beneficial.
Follow routine treatments (including vaccination).

Principal complications requiring the patient to seek urgent medical advice

  • Pain unresponsive to analgesia after 24 hours or severe from the start.
  • Any fever (do not treat at home).
  • Respiratory problems (cough, difficulty breathing, chest pain).
  • Diarrhoea/vomiting and inability to drink.
  • Dehydration (dark, infrequent urine).
  • Anaemia (pale or yellow conjunctivae, pale palms, enlarged spleen).

Routine preventive care

– Prevention of pneumococcal infections
phenoxymethylpenicillin (penicillin V) PO until age 15 years (at least until 5 years):
Children < 1 year: 62.5 mg 2 times daily
Children 1 to < 5 years: 125 mg 2 times daily
Children 5 to 15 years: 250 mg 2 times daily

– Immunization
Ensure that the child’s immunisations are up to date; if not, administer catch up vaccines:

Children
< 5 years

• Hepatitis B, polio, DTP, measles, H. influenzae type B (3 doses)
• Pneumococcal conjugate vaccine, PCV13, or if unavailable PCV7 (3 to 4 doses)
• Meningococcal conjugate vaccine in endemic areas
• At 2 years: pneumococcal 23-valent polysaccharide vaccine, at least 8 weeks after the last PCV13 or PCV7

Children
> 5 years

• Hepatitis B, polio, DT or Td according to age, measles, H. influenzae type B (1 dose)
Pneumococcal conjugate vaccine PCV13 or PCV7 (3 to 4 doses)
• Meningococcal conjugate vaccine in endemic areas

– To support red blood cell production
folic acid PO6 (life-long treatment)
Children < 1 year: 2.5 mg once daily
Children ≥ 1 year and adults: 5 mg once daily

– Malaria chemoprophylaxis (if malaria prevalence ≥ 5%)
mefloquine PO
Children 6 months to 5 years and > 5 kg: 5 mg base/kg once weekly
Do not use to treat malaria.

– Provide nutritional support at hospital discharge.

Routine follow-up of patients

– Between crises, for information:
Children < 5 years: every 1 to 3 months;
Children ≥ 5 years and adults: every 3 to 6 months.

– After a crisis: as often as necessary, according to the clinical course.



Footnotes
Ref Notes
1

Critically ill appearing child: weak grunting or crying, drowsy and difficult to arouse, does not smile, disconjugate or anxious gaze, pallor or cyanosis, general hypotonia.

2 For administration by IV route, ceftriaxone powder should to be reconstituted in water for injection only. For administration by IV infusion, dilute each dose of ceftriaxone in 5 ml/kg of 0.9% sodium chloride or 5% glucose in children less than 20 kg and in a bag of 100 ml of 0.9% sodium chloride or 5% glucose in children 20 kg and over and in adults. [ a b c ]
3 Cloxacillin powder for injection should be reconstituted in 4 ml of water for injection. Then dilute each dose of cloxacillin in 5 ml/kg of 0.9% sodium chloride or 5% glucose in children less than 20 kg and in a bag of 100 ml of 0.9% sodium chloride or 5% glucose in children 20 kg and over and in adults.
4

Always inquire how many transfusions a patient has previously received (risk of iron overload).

5

Do not transfuse whole blood if possible (risk of fluid overload).

6 Iron is contraindicated in patients who have received multiple transfusions. Avoid combined preparations of iron and folic acid.