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Liver involvement in sickle cell disease (SCD) is often referred to as sickle cell hepatopathy (SCH) and is a complication of SCD which may be associated with significant mortality. This review is based on a round-table workshop between paediatric and adult hepatologists and haematologists and review of the literature. The discussion was prompted by the lack of substantial data and guidance in managing these sometimes very challenging cases. This review provides a structured approach for the diagnosis and management of SCH in children and young adults. The term SCH describes any hepatobiliary dysfunction in the context of SCD. Diagnosis and management of biliary complications, acute hepatic crisis, acute hepatic sequestration and other manifestations of SCH are discussed, as well as the role of liver transplantation and haemopoietic stem cell transplantation in the management of SCH.

ObjectiveTo evaluate the acceptability and safety profile of nocturnal long-term oxygen therapy (LTOT) in children with sickle cell disease (SCD) and chronic hypoxaemia.DesignRetrospective cohort study.Patients, setting and interventionChildren with SCD who started LTOT from 2014 to early 2019 in two tertiary hospitals in London, UK were retrospectively enrolled. Patients who started disease-modifying therapies Main outcome measuresMinor and major adverse events during LTOT were reported. Laboratory and clinical data, transcranial Doppler (TCD) scans and overnight oximetry studies performed at steady state within 12 months before and after starting LTOT were compared.ResultsNineteen children (10 males; median age 12 years, range 6–15) were included. Nearly half of them (9/19; 47%) were on hydroxyurea at baseline. No child discontinued LTOT because of intolerance or poor adherence. No major adverse events were reported. Laboratory data did not show significant changes in haemoglobin and reticulocyte count after 1 year of follow-up. No statistically significant change in the incidence of vaso-occlusive pain events was noted (median annual rate from 0.5 to 0 episode per patient/year; p=0.062). Overnight oximetry tests performed while on LTOT showed improvements in all oxygen saturation parameters (mean overnight and nadir SpO2, % of time spent with SpO2 ConclusionLTOT is a safe and feasible treatment option for children with SCD and chronic hypoxaemia.

To detect and characterise different phenotypes of respiratory disease in children and young adults with sickle cell disease (SCD), 11 lung function and haematological biomarkers were analysed using k-means cluster analysis in a cohort of 114 subjects with SCD aged between 5 and 27 years. Three clusters were detected: cluster 1 had elevated pulmonary capillary blood volume, mixed obstructive/restrictive lung disease, hypoxia and moderately severe anaemia; cluster 2 were older patients with restrictive lung disease; and cluster 3 were younger patients with obstructive lung disease, elevated serum lactate dehydrogenase and bronchodilator reversibility. These results may inform more personalised management strategies to improve outcomes.

Background and objectives The porphyrias are a group of rare, mainly inherited, diseases caused by a deficiency of one of the enzymes of the haem biosynthesis pathway. The biochemical hallmark of an acute attack is an increase in urine porphobilinogen (PBG), together with an increase in urinary excretion of δ-aminolaevulinic acid (ALA) and total urine porphyrins (TUP). In patients with acute intermittent porphyria (AIP) the concentrations of the porphyrin precursors are thought to remain elevated for many years following an acute attack, although this has not been well documented. Methods We measured urine ALA, PBG and TUP excretion in 20 patients with AIP following an attack of acute porphyria over a time period of 3 months to 23 years after their last documented acute attack. Results We showed that urinary concentrations of all metabolites remain elevated for many years. The urinary half life of TUP was 5.3 years, ALA 7.7 years and PBG 10.6 years. Even after 20 years, PBG concentrations remained elevated above the normal range. Conclusions Our study highlights the difficulties of using urinary analysis for diagnosing recurrent attacks, and also raises important questions about the pathophysiology of the condition.

Objective: To assess the role. of transcranial Doppler (TCD) scanning in assessing the risk of stroke in children with HbSC disease. TCD scanning has an established role in primary stroke prevention in sickle cell anaemia (HbSS) but its value in HbSC is unknown. Design: A retrospective audit of routinely performed TCD scans and routinely collected clinical data. Setting: A paediatric sickle cell clinic in a teaching hospital in South London. Patients: 46 children with HbSC disease who had routinely performed TCD scans and steady state blood tests. Main outcome measures: The time averaged mean of the maximum velocity (TAMMV) in the middle cerebral artery circulation, correlated with clinical and laboratory data. Results: The mean TAMMV was 94cm/s, with a 98th centile of 128cm/s. This is significantly less than the published ranges for HbSS, with a mean reading of 129cm/s. One child had a stroke at the age of 5 years, when her TAMMV was measured at 146cm/s. Conclusions: Further studies are needed to assess stroke risk in HbSC, but we suggest that TCD measurements are potentially useful in this condition, and that readings greater than 128cm/s are abnormally high and warrant further investigation.

Aim Accurate measurement of Hb saturation is essential in the care of children with sickle cell disease (SCD). The gold standard of Hb saturation measurement is by ABG with co-oximetry. Minute-by-minute changes are detected with pulse oximetry (SpO2). SpO2 shows good correlation to ABG co-oximetry in well patients with normal Hb. SCD patients represent a different population: previous small studies have shown discrepancies in calculated ABG and SpO2 Hb saturations. SpO2 may be falsely low due to high carboxyhaemoglobin and metahaemaglobin levels following heme catabolism, or high due to hyperbilirubinaemia. Both occur in acute and chronic haemolysis. With treatment decisions in acute and ambulatory settings driven by bedside SpO2, inaccuracies can result in mismanagement. Earlobe blood gas (EBG) co-oximetry is an alternative better tolerated method of measuring Hb O2 saturation in arterialised capillary blood (SaO2), with good correlation to ABG measurements. We sought to investigate the correlation between SpO2 and SaO2 measured by EBG co-oximetry in ambulatory SCD children. Methods We retrospectively reviewed paediatric SCD patients attending a UK tertiary sickle-respiratory clinic from February 2012–August 2015, and who had simultaneous EBG and SpO2 measurements. Positive difference results from SpO2 value greater than EBG SaO2. Results We identified 39 simultaneous paired SaO2 and SpO2 readings from 33 patients (52% male, median age 10years, range: 5–17). Mean difference between readings was –0.7% (Figure 1 and 2). In 23% of cases, difference was >±2%. SaO2 was overestimated in one-third and underestimated in two-thirds. Of 17 hypoxaemic measurements (SpO2 Conclusion Pulse oximetry as a measure of Hb oxygen saturation was inaccurate in a significant proportion of ambulatory SCD children. SpO2 tended to be lower than actual SaO2 as measured with EBG, with SpO2≥94% more likely to predict true result than SpO2

Haematopoietic stem cell transplantation from alternative donors is curative for children with sickle cell disease, but risk of death is high. David Rees and colleagues call for greater caution in its use

Peripheral venous access in children with sickle cell anaemia (SCA) requiring regular blood transfusions can become difficult over time. Previous reports have suggested the use of totally implantable venous access devices, Portacaths (PAC) in this patient group are associated with unacceptable high rates of complications. We present our experience in seven children with SCA over a 9-year period. Seven devices were placed for a total of 9754 PAC days during the study period. The median age at insertion was 6.3 years (range 3-15 years). The rate of PAC associated infection was 0.2 per 1000 PAC days. There were no episodes of thrombosis. The median length of time in situ during the study period was 3.7 years (range 1.3-7.5 years). Our experience highlights the safe and reliable use of PAC in children with SCA requiring regular blood transfusions when venous access has become a major problem.

Background Sickle Cell Disease (SCD) affects about 1 in 1,900 children born in the UK. Respiratory morbidity affects children as well as adults with SCD and the burden may have been underestimated in the past. The published literature suggests that asthma, airway hyper-reactivity and sleep disordered breathing (SDB) are common in children with SCD. Furthermore asthma and SDB have been reported to be associated with acute chest syndrome (ACS) and vaso-occlusive crises (VOC). Children with SCD are increasingly referred to our respiratory clinic in a tertiary paediatric centre in the UK. We did an analysis of a sample of these children to gain some preliminary insights into the problem. Method A retrospective observational study was carried out using data from children with SCD who had been referred to our tertiary paediatric respiratory clinic between 1 st September 2009 and 31 st August 2014. Data was collected from electronic patient records and electronic investigation results. Results 54 patient records were evaluated. The mean age of the children was 11 years and 54% were male. The most common reason for referral was low oxygen saturation on pulse oximetry (23/54). Surprisingly, asthma and wheeze were uncommon reasons for referrals comprising only 7/54 (Figure 1). However, of all the patients 48% were discovered to have asthma and 52% had SDB. In those patients who underwent lung function testing an abnormal result was reported in 60% (25/42). In addition 71% of children who had a sleep study had an abnormal result (35/49). No association between ACS or VOC events in those patients with asthma or SDB was noted but this could have been due to the small numbers. Conclusion In this sample of children with SCD referred mainly because of low oxygen saturation, the high proportion with an abnormal sleep study and SDB might have been expected. However, the relative paucity of reported wheeze and exercise intolerance despite large numbers with abnormal lung physiology suggested that conditions such as asthma may be unrecognised in these patients.

Aims Sickle cell disease is the most common inherited disorder in African and Caribbean populations. Restrictive lung function abnormalities become increasingly common in older patients and indeed are characteristic of sickle chronic lung disease. Young children with SCD, however, frequently have obstructive lung function abnormalities. It is not clear whether the obstructive abnormalities are due to asthma or the elevated pulmonary capillary blood volume seen in SCD children because of their chronic anaemia. Such data are essential to determine the most effective preventative strategies. Hence, our aim was to investigate whether blood transfusion in SCD children acutely increased pulmonary capillary blood volume (PCBV) and this was associated with increased airways obstruction. Methods Measurements of respiratory system resistance and spirometry were made before and after blood transfusion in 18 children, median age 14.2 (6.6–18.5) years. The respiratory system resistance was measured using impulse oscillometry and a frequency of 5 Hz (Rrs5) and was used to assess small airway function. Lung function results were expressed as the percent predicted for height. Pulmonary capillary blood volume was measured using the single breath-hold method for gas transfer for carbon monoxide (DLCO) and nitric oxide (DLNO). Pulmonary membrane diffusing capacity (DMCO) and pulmonary capillary blood volume (PCBV) were then determined using the Roughton-Forster model. Results Post transfusion, the median Rrs5 increased from 127.4 to 141.3% predicted for height (p Conclusion Significant increases in pulmonary capillary blood volume and respiratory system resistance occurred immediately following blood transfusion in children with SCD. Furthermore, the increase in respiratory system resistance significantly correlated with the increase in pulmonary capillary blood volume. These results provide evidence of a potential interaction between the increased pulmonary capillary blood volume and pulmonary function abnormalities seen in SCD children.

Aims Children with sickle cell disease (SCD) often have obstructive lung function abnormalities. Those abnormalities could be due to asthma, but there is conflicting evidence regarding whether asthma is more common in SCD children. Another explanation for the airways obstruction is the increased pulmonary blood volume resulting from chronic anaemia in SCD patients. In asthmatics, exhaled nitric oxide (F eNO ) is elevated. F eNO , however, can also be raised due to increased alveolar production. Our aim, therefore, was to determine if airway or alveolar NO production differed between SCD children and ethnic and age matched controls. Such data would inform the debate as to whether airways obstruction in SCD is due to asthma or not and hence inform treatment strategies. Methods African or Caribbean children with SCD (homozygous for sickle cell haemoglobin (HbSS)) and ethnic and age matched controls were recruited. Exhaled nitric oxide was measured at multiple flow rates to derive the total maximal airway NO flux and the alveolar NO concentration using a two-compartment model. The transfer factor for nitric oxide (DLNO) was measured using the single-breath method and used withthe alveolar NO concentration to derive the rate of alveolar NO production. The respiratory system resistance (Rrs) was measured using impulse oscillometry and a frequency of 5 Hz was used to assess small airway function. Lung function was also assessed by spirometry and static lung volumes and the transfer factor for carbon monoxide were measured. All results were expressed as the percent predicted for height. Results The 18 SCD children compared to the 18 controls had a higher respiratory system resistance (p = 0.0008), alveolar NO production (p = 0.0224) and pulmonary blood flow (p eNO and respiratory system resistance in either group, but in the SCD children there were correlations between pulmonary blood volume and both alveolar NO production (p = 0.0006) and concentration (p Conclusions Airway NO flux was not elevated in the SCD children nor correlated with airways obstruction, suggesting that airways obstruction, at least in some SCD children, is not due to asthma.

Introduction Sickle cell disease (SCD) causes lifelong morbidity and reduced life expectancy. Resting hypoxaemia and intermittent nocturnal oxygen desaturation are often seen in children with SCD, which may contribute to morbidity associated with vaso-occlusive episodes. Treatment with hydroxyurea reduces the frequency and severity of vaso-occlusive episodes 1 but the impact of hydroxyurea on oxygen saturation and sleep apnoea is unknown. Objective To look for any difference in baseline oxygen saturation asleep and awake and the frequency of intermittent nocturnal desaturation after starting hydroxyurea in children with SCD. Methods A retrospective review of children who were commenced on hydroxyurea between March 2006 and July 2014 attending two UK sickle-respiratory clinics. Data was collected from overnight sleep studies and averaged pulse oximeter spot check recordings in clinic notes when awake from a) 6 months before starting hydroxyurea and b) up to 2 years after. Lung function and haemoglobin changes were also noted over the same time periods. Results Forty six children (25 male) with a median age of 10 years (range 5–19 years) were started on hydroxyurea. Haemoglobin and HbF rose significantly on hydroxyurea as expected (Table 1). After starting hydroxyurea the average overnight oxygen saturation increased from median of 93.5% to 95.2% (p = 0.01) and the median daytime spot oxygen saturation rose from 93.5% to 96.3% (p = 0.001). There was no significant change in the median intermittent nocturnal 3% oxygen desaturation index (ODI), nocturnal PCO 2 or spirometry. Conclusion In children with SCD, the use of hydroxyurea was associated with a significant increase in awake and nocturnal baseline oxygen saturation, but no change in intermittent nocturnal desaturation indices or lung function. This preliminary data suggests that improving oxygen saturation may be an important outcome of hydroxyurea therapy with potential benefits in reducing not only vaso-occlusive crises but future respiratory morbidities. This hypothesis would need to be tested by a prospective multicenter trial. Reference 1 Charache S, Terrin ML, Moore RD, et al . Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995; 332 :1317–1322

Aims To prospectively undertake longitudinal assessment of lung function in children with sickle cell disease (SCD) and similar aged and ethnic matched controls. Our aim was to test the hypotheses that lung function in SCD children, but not controls would deteriorate with increasing age and the rate of decline would be greater in younger children who are more likely to have suffered acute chest syndrome (ACS) episodes. Methods Two cohorts of SCD children and age and ethnic matched controls were recruited. Cohort one (47 SCD children and 26 controls) had a median age of 8.8 years at recruitment and were followed for two years. Cohort two (45 SCD children and 26 controls) were recruited at an older age (median age 10.2 years) than cohort one (p = 0.007) and were followed for ten years. Forced expiratory volume in one second (FEV 1 ), vital capacity (VC), forced expiratory flow between twenty-five and seventy-five% of VC (FEF 25–75 ), total lung capacity (TLC) and residual volume (RV) were measured at recruitment and at the end of follow-up. Results In both groups of SCD children, but in neither control group, lung function declined significantly. The rate of decline was greater in cohort one than cohort two for FEV 1 (p = 0.008), VC (p = 0.001), FEF 25–75 (p = 0.030), TLC (p = 0.004), and RV (p = 0.043). During follow-up, ACS episodes were more common in cohort one than cohort two (one episode per 1.93 patient/years versus one episode per 12.6 patient/years) p Conclusions Lung function deteriorated in SCD children compared to similar aged and ethnic matched controls. The most rapid period of deterioration took place during early childhood when ACS episodes were more common. Our results suggest that treatment strategies to prevent ACS episodes need to be started in young SCD children if they are to be most effective in preventing the decline in lung function.

Summary points Sickle cell disease is characterised by unpredictable episodes of acute illness, progressive organ damage, and a lack of effective treatments. It is one of the most common inherited conditions, although its prevalence varies widely. Median life expectancy is currently 40-60 years in high income countries but much less in low income areas.1 2 It is associated with protean clinical complications. Patients present to all medical specialties and increasingly to general practitioners. This review aims to provide an evidence based update on how to manage patients with this disease in the community. It does not consider sickle cell trait, which is largely asymptomatic. #### Sources and selection criteria We searched Medline, the Cochrane Database, and ClinicalTrials.gov using the term “sickle” together with certain complications including pain, infection, enuresis, renal failure, spleen, acute chest syndrome, leg ulcers, and stroke. Preference was given to randomised clinical trials, and when these were unavailable large case series were sought. We prioritised newer studies over older ones. Sickle cell disease …

The aim of our review was to evaluate the evidence for and against folic acid supplementation in sickle cell disease. Folic acid has been both widely prescribed and hotly debated for the last four decades. We undertook an extensive literature based review with the aim of evaluating the clinical benefits of this supplementation and its implications on future paediatric practice. Comprehensive scientific search engines were used to locate articles published up to June 2011. A wide range of search terms were used, and article references and citations were reviewed for further leads. Studies in support of folic acid supplementation have cited low serum and erythrocyte folate levels in paediatric sickle cell patients, high incidence of megaloblastic anaemia, patient desire for folic acid and the positive effects of supplementation including; reversal of developmental delay, reduced dactylitis and reduction of homocysteine levels leading to reduced cardiovascular, stroke and venous thrombosis risk. Studies against folic acid supplementation conversely found that folate is not deficient in patients, megaloblastic change is uncommon and both these parameters are not improved with supplementation. They have shown that folic acid does not lead to improvements in haemoglobin, growth characteristics, infections, splenic sequestration and dactylitis. Possible dangerous effects of supplementation are also referred to including increased priaprism, increased twin pregnancy rates and the risk of masking cobalamin deficiency with consequent neuropsychiatric manifestations. These studies also found that homocysteine levels are not lower in sickle cell patients and cardiovascular risk is not reduced with supplementation. The conflicting results may be due to genetic polymorphisms in folic acid/homocysteine metabolism between patients, inconsistent supplementation doses and various ethnic group representations in the papers analysed. Drawing definitive conclusions is difficult due to the small number and heterogeneous nature of the studies and our review has emphasised the need for more prospective, sufficiently powered, research in this field. Till then, the safest clinical practice would be to individualise folic acid treatment for patients based on their needs and comorbidities whilst continuing to encourage compliance with more evidence based medications including Penicillin V and hydroxyurea.