Sickle cell disease: diagnosis and health maintenance: Viva

This is a newborn-screen diagnosis of sickle cell anaemia, HbSS, in a well eight-week-old boy. The structured oral runs from the confirmation of the diagnosis through the molecular basis, the immediate prophylaxis, the hydroxyurea decision, and the stroke-prevention strategy, and it ends with the trial evidence. [5]

Opening: confirm the diagnosis

Examiner. The newborn screen shows an FS pattern. What does that mean, and how do you confirm it? [5]

Candidate. The FS pattern on high-performance liquid chromatography means the child has haemoglobin F and haemoglobin S with little or no haemoglobin A, which is the pattern of HbSS, sickle cell anaemia. I confirm it with a repeat test on a fresh sample by the same method, and I do not need further testing unless the result is ambiguous, in which case deoxyribonucleic acid testing of the HBB gene settles the mutation. The child is well at eight weeks because fetal haemoglobin protects the cell, and the complications begin only as it falls through the first year. [5]

Branch 1: the molecular basis

Examiner. Tell me the molecular lesion and why it matters. [2]

Candidate. The mutation substitutes a valine for the glutamate at the sixth position of the beta-globin chain, written as p.Glu6Val, in the HBB gene. The valine is hydrophobic, and when haemoglobin S gives up its oxygen the valine exposes a sticky patch that docks into a pocket on a neighbouring molecule, so the haemoglobin S polymerises into long fibres that stretch the cell into the rigid sickle. The sickled cell blocks small vessels, causing the pain of vaso-occlusion, and it breaks down, causing the chronic haemolytic anaemia. [2]

Examiner (probe). And why does fetal haemoglobin protect the cell? [2]

Candidate. Fetal haemoglobin does not carry the sickle mutation, and it dilutes the concentration of haemoglobin S in the cell, which raises the threshold for polymerisation. This is why the newborn is well and why hydroxyurea works, because it raises the fetal haemoglobin level. [2]

Branch 2: what you start now

Examiner. The boy is eight weeks old and well. What do you start today? [5]

Candidate. I start oral penicillin V prophylaxis now, at a dose of 125 mg twice daily, because the child is under three years. The PROPS trial of Gaston and colleagues showed that penicillin reduced pneumococcal sepsis by 84 percent, and the dose is 125 mg twice daily under three years and 250 mg twice daily at three years and over, continued to five years. I enrol him in the sickle cell clinic, give the parents a written emergency plan for fever above 38.5 degrees Celsius, and teach them to palpate the spleen for the pallor and lethargy of acute sequestration. [1][5]

Examiner (probe). And the immunisations? [5]

Candidate. He receives the routine childhood vaccines, 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, because he develops functional asplenia in the first years of life. [5]

Branch 3: hydroxyurea

Examiner. When do you start hydroxyurea, and how do you monitor it? [5]

Candidate. I offer hydroxyurea from nine months of age to every child with HbSS, regardless of severity, 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. The Multicenter Study of Hydroxyurea showed in adults that it reduced the painful crises, the acute chest syndrome, and the transfusion requirement, and it works by raising the fetal haemoglobin. I watch for myelosuppression, a neutrophil count under 2.0 times ten to the nine per litre, and I hold or reduce the dose when it appears. [2][5]

Branch 4: stroke prevention

Examiner. How do you prevent stroke in this boy? [3]

Candidate. I screen with an annual transcranial Doppler from ages two to sixteen, and if the time-averaged mean velocity reaches 200 cm per second or more, I start a chronic transfusion programme to keep the haemoglobin S under 30 percent. The STOP trial of Adams and colleagues in 1998 showed that this reduced the risk of a first stroke by about 90 percent. The STOP II data showed that stopping the transfusion once the Doppler normalised led to reversion and stroke, so I continue the transfusion or switch to hydroxyurea by the TWiTCH protocol, never simply stop. [3][5]

Examiner (probe). Tell me about TWiTCH. [7]

Candidate. The TWiTCH trial of Ware and colleagues in 2016 showed that hydroxyurea was non-inferior to chronic transfusion in children already transfused for at least 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 transfusion thus becomes a bridge, and the iron is reduced by the phlebotomy that follows the switch. [7]

Closing: the whole package

Examiner. Sum up the outlook for this boy. [5]

Candidate. With newborn screening, penicillin prophylaxis, full immunisation, hydroxyurea from nine months, and annual transcranial Doppler with transfusion for the abnormal result, this boy can expect to reach adulthood in good health, with a stroke-free childhood and a brain intact. The chief threats have shifted to the adult years, and my job now is to keep him on the package and to plan his transition to adult care in good time. [5]