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DARJEELING, INDIA Children go home from school (2010).
© PAVEL SVOBODA PHOTOGRAPHY / SHUTTERSTOCK.COM
In 1910 Herrick was the first to describe ‘peculiar elongated and sickle-shaped red blood corpuscles’ in a patient presenting with respiratory distress and severe anaemia, currently known as sickle cell anaemia (SCA).[1] Worldwide it is the most common congenital haemolytic anaemia, affecting an estimated 4.4 million patients. Roughly 300,000 infants are born with SCA each year, the majority in sub-Saharan Africa but also in India, Saudi Arabia and some Mediterranean countries. Migration brought this heritable disease to the Caribbean region (slave trade), the Americas and the rest of the world.
Genetics and pathophysiology
Haemoglobin, the oxygen-carrying protein in blood, consists of a tetramer with 2 α- and 2 β- globin chains. A gene mutation on the short arm of chromosome II is responsible for the replacement of glutamic acid by valine in the β- globin chain of the haemoglobin (βs). Upon red cell deoxygenation, this HbS haemoglobin polymerizes into insoluble intracellular fibers causing the sickle cell deformity resulting in membrane damage and ultimately haemolysis. The homozygous form (HbSS or βsβs) reduces the red cell life span from 120 to ± 20 days causing anaemia despite increased bone marrow activity.
Sickle cell in a blood smear
Heterozygosity for βs (HbAS or sickle cell trait) is the mostly asymptomatic carrier state with a survival advantage in areas with high presence of malaria. Other forms of sickle cell disease with variable severity result from combinations of βs with for example haemoglobin C (HbSC or βsβc) or thalassemias (βsβ0-thalassemia or βsβ+-thalassemia), or the so called compound heterozygous states.
The microvascular perfusion of vital organs is impaired by a cascade that is set in motion by damaged sickle cells. As they become dehydrated, inflexible and abnormally adhesive, interactions between red cells, activated leukocytes, platelets and vascular endothelial cells occur. A complex interplay between plasma factors, increased expression of adhesion receptors, a pro thrombotic state and endothelial dysfunction will ultimately result in both micro- and macrovascular obstruction resulting in ischaemic organ injury with accumulating loss of function.
Two cases are presented demonstrating the impact of SCA.
Case 1
A 2 year old boy visited Curacao on vacation from Surinam presented at the paediatric outpatient clinic with swollen and extremely painful hands and feet since one day. No fever or trauma was reported. His past medical history was uneventful. On examination he had a temperature of 37 °C, was alert, in a well hydrated and nutritional state and almost continuously crying. The dorsum of both hands and feet were painful, cushiony, and swollen with pencil like fingers. Joints were not affected, no edema was noticed, No signs of meningism, heart and lungs normal, abdomen liver and spleen not palpable. Based on the typical presentation of dactylitis (‘hand-foot syndrome’), he was admitted for intravenous hyperhydration and analgesic treatment. The diagnosis was confirmed by high pressure liquid chromatography (HPLC): sickle cell anaemia HbSS. He recovered within 3 days.
Case 2
A 4 year old boy was rushed to the emergency policlinic by his parents. Sadly he was found dead on arrival. The history revealed that he had been referred to the paediatric policlinic 2 years ago with the diagnosis of HbSS. The family had an illegal status on Curacao and preferred to keep a ‘low profile’ to avoid extradition to Haiti, their country of origin. Regretfully, healthcare insurance is impossible for illegal citizens, which was yet another reason for them not to visit the paediatric outpatient clinic. Although the boy had fever for 2 days and became lethargic, no medical care was sought. No vaccinations or any other medications were previously administered.
Post mortem examination revealed S. pneumoniae sepsis with meningitis. No pneumococcal sub typing was performed. SCA HbSS was confirmed.
Comment
Case 1: dactylitis, vaso-occlusive ischaemia and infarction of metacarpals and phalanges, is often the first clinical sign of SCA in paediatric patients under 5 years of age. New-born screening, now implemented in many countries, could have detected the disease right after birth with the possibility of early information to the parents and timely implementation of preventive measures such as pneumococcal vaccination.
Case 2: overwhelming sepsis and meningitis due to especially encapsulated micro-organisms are – although less frequent – still major complications in SCA patients. The main cause is a process of auto-splenectomy due to infarction of the spleen with loss of its filtration function, starting 3 months after birth and completed at around 5 years of age. Daily penicillin prophylaxis for children with SCA was introduced after this intervention was found to make a remarkable difference in sepsis morbidity and mortality. For qualifying patients, prophylaxis was adjusted to a shorter period (5 years) after new studies showed this was reasonable.[2,3]
Both cases highlight the importance of early detection and thorough information about the disease with regular follow up at a paediatric-haematologic facility.
Sca variability
One of the most striking observations in SCA is the clinical heterogeneity of the disease between patients within a family, regions and countries, based on a wide variability of phenotypes that sometimes hardly show any symptoms. The combination with α-thalassemia may decrease the severity of specific SCA related complications, whereas worsening others. A persisting high percentage of haemoglobin F (HbF) is by far the most powerful modifier of SCA, as this reduces the sickling process. Patients with the ‘high persistent foetal gene’ often have more than 20% HbF and are generally less affected by the disease.[4] Therapy with oral hydroxyurea is aimed at increasing HbF.
Symptoms and complications
- Vaso-occlusive (pain) crises (VOC) occur in bones of hand and feet of younger children; 7 years and older in long bones and vertebrae, usually without any physical signs. Triggers are dehydration, cooling off, infections, and ‘unknown’.
Although far less common, avascular necrosis (mostly in femoral heads) should be excluded as well as osteomyelitis that may occur in any bone (often Salmonella and Staphylococcus species). VOC in the mesenteric vessels may also cause abdominal pain mimicking acute appendicitis. - Infections due to loss of splenic function. This immune vulnerability requires that febrile patients should be evaluated without delay to exclude any signs of sepsis, pneumonia and meningitis and be started on broad spectrum antibiotics immediately, awaiting lab results.
- Splenic sequestration in the first 5 years of life, as a result of sudden massive trapping of erythrocytes in the splenic sinusoids, with (increased) enlargement of the spleen causing severe anaemia, hypovolaemia and possible shock.
- Transient aplastic anaemia caused by human parvo virus B19 infection, which by temporarily interfering with erythrocyte production in the bone marrow may result in severe anaemia in patients with an already reduced erythrocyte lifespan. Erythrocyte transfusions are life-saving.
- Acute chest syndrome is an acute pulmonary disease in patients with SCA, often accompanied by fever, chest pain, dyspnoea or tachypnea. Chest X-rays may show a new pulmonary infiltrate. In young children there is often an association with viral respiratory infections. Treatment is mainly supportive. The aetiology is not fully understood.
- Stroke (ischemic more than hemorrhagic) may occur due to occlusion or haemorrhage of large intracranial vessels, sometimes preceded by transient ischemic attacks. MRI and MR-angiography are required to determine the extent of affected brain tissue. Immediate (exchange) blood transfusions are critical in limiting further damage, while chronic transfusions may lower the rate of recurrence by decreasing the amount of HbS below 30%. Transcranial Doppler (TCD) examination may identify children with a high risk of stroke (blood flow velocity in de medial cerebral artery > 200 cm/sec.).
- Cholelithiasis with bilirubin gallstones is a common complication in children with SCA and should be ruled out in any event of abdominal pain. Symptomatic gallstones probably require elective laparoscopic cholecystectomy to avoid cholecystitis.
- Priapism, a painful erection of the penis lasting longer than 4 hours is a medical emergency. Treatment with epinephrine, hyperhydration and analgesics as well as aspiration and irrigation of the corpora cavernosa are used for fast relief.
- Retinopathy with possible loss of visual acuity is mainly seen in older children (>10 years) with HbSC. Retinal artery occlusion may cause a proliferative retinopathy, vitreal haemorrhage and retinal detachment. Laser photocoagulation may prevent further damage.
- The renal medulla with high osmolarity facilitates erythrocyte sickling with vaso-occlusion of the vasa recta, causing loss of urine concentration with polyuria, promoting dehydration and enuresis. Papillary necrosis due to renal ischaemia may lead to haematuria.
Treatment
More than 100 years of sickle cell research has resulted in a much deeper insight into the pathophysiology of SCA. Besides hydroxyurea as the currently most effective and available medication, several disease modifying drugs are currently in the pipeline. These are targeted at cell adhesion, inflammatory pathways, up regulation of HbF, haemoglobin polymerization and sickling, coagulation and platelet activation.[5]
At present, the only cure for SCA is hematopoietic stem cell transplantation, but this procedure is limited by the frequent lack of an HLA compatible donor and a possible graft versus host rejection. In general, this option is therefore limited to those with severe complications of SCA.[6]
Summary
SCA is a disease with a widely variable phenotype. Guidelines should therefore be adjusted and reflect the local experience with disease severity and complications.[7] The ultimate cure should be easy to apply all over the world (also cost wise, as the majority of patients live in areas with a lower socio-economic status). In the meantime, prevention – family planning/counselling, newborn screening, regular medical follow up (TCD and retinopathy screening), increased infection risk awareness and vaccination (conjugated pneumococcal vaccine), optimized hydration status, avoiding hypoxic environments and strong cooling off – is still our best bet, as this may decrease morbidity and improve life expectancy.
References
- Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anaemia. Arch Intern Med 1910; 6: 517-2
- Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anaemia. N Engl J Med 1986; 314: 1593-9
- Falletta JM, Woods GM, Verter JI, et al. Discontinuing penicillin prophylaxis in children with sickle cell anaemia. Prophylactic Penicillin Study II. J Pediatr 1995;127: 685-90
- Steinberg MH. Clinical variability in sickle cell anaemia in Uptodate 2016
- Telen MJ. Beyond Hydroxyurea: new and old drugs in the pipeline for sickle cell disease. Blood 2016; 127: 810-819
- Quin CT. Sickle cell disease in childhood from newborn screening through transition to adult medical care. Pediatr Clin N Am 60 2013: 1363-1381
- Schnog JB et al. Sikkelcelziekte een praktische handleiding. 2006 ISBN 90-8523-110-8
