Sickle cell disease: diagnosis and health maintenance: SAQ

This boy has sickle cell anaemia, the HbSS genotype, found on newborn screening before he has been ill at all. The haemoglobin pattern of FS on high-performance liquid chromatography, with haemoglobin F and haemoglobin S and little or no haemoglobin A, is the classic pattern of HbSS in the newborn, and the repeat test confirms it. The newborn is well because fetal haemoglobin protects the cell, and the complications begin only as the fetal haemoglobin falls through the first year. The task now is to keep him well. [5]

Question 1 (10 marks)

Outline the diagnosis and the immediate health-maintenance plan for this eight-week-old boy, justifying each step with the relevant evidence. [5]

A full-mark answer addresses the genetic diagnosis, the penicillin prophylaxis with exact doses, the immunisation plan, the parental education, and the timing of the next interventions. [5]

Diagnosis and counselling (2 marks). The FS pattern on high-performance liquid chromatography is diagnostic of HbSS, confirmed on repeat testing, and no further test is needed unless the result is ambiguous, in which case deoxyribonucleic acid testing of the HBB gene settles the mutation. The disease is autosomal recessive, the p.Glu6Val substitution, and two carrier parents have a one in four chance in each pregnancy, so the family is counselled on the inheritance and the option of testing the siblings and future pregnancies. [5]

Penicillin prophylaxis (3 marks). Penicillin V prophylaxis is the single most important early intervention, and the PROPS trial of Gaston and colleagues showed it reduced pneumococcal sepsis by 84 percent. It is started by two months of age, which is now, and the dose is 125 mg orally twice daily under three years of age, continued to five years. The parents are taught that any fever above 38.5 degrees Celsius is an emergency that needs prompt assessment and a parenteral antibiotic such as ceftriaxone, because the child develops functional asplenia in the first years of life. [1][5]

Immunisation (2 marks). The routine childhood immunisations are given, and on top of them the encapsulated-organ cover: the pneumococcal conjugate vaccine on schedule plus the 23-valent polysaccharide vaccine at two years and again five years later, the meningococcal ACWY and serogroup B vaccines, Haemophilus influenzae type b, and the annual influenza vaccine. The parents are taught to palpate the spleen and to bring the boy in at once for pallor, lethargy, or a rapidly enlarging spleen, the signs of acute splenic sequestration. [5]

Future interventions and counselling (3 marks). Hydroxyurea is offered from nine months of age at a starting dose of 20 mg per kg per day, regardless of severity, with a full blood count every four weeks. The annual transcranial Doppler begins at two years and runs to sixteen, with chronic transfusion to keep the haemoglobin S under 30 percent if the velocity reaches 200 cm per second or more. The family is enrolled in the sickle cell clinic, given a written emergency plan, and the parents are reminded that with this package the boy can expect to reach adulthood. [2][3]

Question 2 (10 marks)

Explain how hydroxyurea and transcranial Doppler with transfusion change the trajectory of sickle cell disease, and critically appraise the trial evidence. [2]

A full-mark answer reproduces the mechanism and appraises the three trials by what they showed and what they changed. [3]

Hydroxyurea (4 marks). Hydroxyurea raises the fetal haemoglobin level, which dilutes the haemoglobin S and blocks its polymerisation, and it lowers the white cell count, which reduces the inflammation of vaso-occlusion. The Multicenter Study of Hydroxyurea, published by Charache and colleagues in 1995, showed in adults that the drug reduced the frequency of painful crises, the acute chest syndrome, and the transfusion requirement, and the long-term follow-up confirmed the safety in children from infancy. The current recommendation is to offer it to every child with HbSS from nine months, at a starting dose of 20 mg per kg per day escalated by 5 mg per kg per day every eight weeks to the maximum tolerated dose, with a full blood count every four weeks to watch for myelosuppression. [2][5]

Transcranial Doppler and transfusion (4 marks). The transcranial Doppler measures the velocity of blood in the cerebral arteries, and a time-averaged mean velocity of 200 cm per second or more is a pre-stroke state. The STOP trial of Adams and colleagues in 1998 showed that chronic transfusion reduced the risk of a first stroke by about 90 percent in children with an abnormal Doppler, and the annual screening from ages two to sixteen became the standard. The transfusion keeps the haemoglobin S under 30 percent, given every three to four weeks. The STOP II data showed that stopping the transfusion once the Doppler normalised led to reversion and stroke, so the transfusion is continued or switched to hydroxyurea by the TWiTCH protocol, never simply stopped. [3][5]

The TWiTCH strategy (2 marks). The TWiTCH trial of Ware and colleagues in 2016 showed that hydroxyurea was non-inferior to chronic transfusion in children already transfused for a year with a normal Doppler and no silent infarct, so many children can switch to hydroxyurea and stop the iron overload of chronic transfusion. The chronic transfusion thus becomes a bridge rather than a lifetime commitment, and the iron is reduced by the phlebotomy that follows. The fellow who understands these three trials, the PROPS trial for penicillin, and the package they together build, has the evidence base of modern sickle cell health maintenance. [7]