High Prevalence of Hemophagocytic Lymphohistiocytosis in Acute Liver Failure of Infancy.

OBJECTIVES: To investigate the prevalence of hemophagocytic lymphohistiocytosis (HLH) syndrome in pediatric acute liver failure (PALF) of infancy and assess the diagnostic role of rapid immunologic tests, genotype/phenotype correlations, and clinical outcomes. STUDY DESIGN: We retrospectively analyzed 78 children with PALF aged <24 months referred over almost 2 decades. The studied patients with a phenotype of HLH syndrome had a comprehensive immunologic workup, including additional genetic analysis for primary immunologic causes. RESULTS: Thirty of the 78 children had the HLH phenotype and underwent genetic assessment, which demonstrated positive findings in 19 (63.3%), including 9 (30%) with biallelic primary HLH mutations and 10 (33.3%) with heterozygous mutations and/or polymorphisms. The most common form of primary HLH was familial hemophagocytic lymphohistiocytosis (FHL)-2, diagnosed in 6 children, 4 of whom had a c.50delT (p.Leu17ArgfsTer34) mutation in the PRF1 gene. Three patients with primary HLH received genetic diagnoses of FHL-3, Griscelli syndrome, and LRBA (lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing) protein deficiency. Overall mortality in the series was 52.6% (10 of 19), and mortality in children with a documented biallelic pathogenic HLH mutation (ie, primary HLH) was 66.6% (6 of 9). Two children underwent liver transplantation, and 4 children underwent emergency hematopoietic stem cell transplantation; all but 1 child survived medium term. CONCLUSIONS: Primary HLH can be diagnosed retrospectively in approximately one-third of infants with indeterminate PALF (iPALF) who meet the clinical criteria for HLH, often leading to their death. The most common HLH type in iPALF is FHL-2, caused by biallelic mutations in PRF-1. The clinical relevance of observed heterozygous mutations and variants of uncertain significance requires further investigation. Prompt hematopoietic stem cell transplantation could be life-saving in infants who survive the liver injury.

What is the role of chest X-ray imaging in the acute management of children with sickle cell disease?

Children with sickle cell disease (SCD) frequently present to hospital acutely unwell and are often exposed to diagnostic chest X-rays (CXRs). Little evidence exists to determine when CXRs are clinically useful. Using electronic hospital records, we audited CXR use in children aged 0-18 who presented to hospital over the past 10 years in both an inpatient and emergency department setting. From a total of 915 first CXRs, only 28·2% of CXRs (n = 258) had clinically significant findings that altered management or final diagnosis. Of these abnormalities, consolidation represented 52·3%, effusion 8·9%, cardiomegaly 8·4% and sickle cell-related bone changes 6·3%. Indications for CXR of respiratory distress (OR = 3·74, 95% CI 2·28-6·13), hypoxia (OR = 1·86, 95% CI 1·50-2·31) and cough (OR = 1·64, 95% CI 1·33-2·02), were more likely to have significant CXR findings. Patients who had higher peak fever (38·4°C vs. 37·4°C, P = 0·001), higher peak CRP (156·4 vs. 46·1, P < 0·001) and higher WCC (20·2 vs. 13·6, P < 0·001) were more likely to have clinically significant abnormalities on CXR. We found a decision tool using either hypoxia, cough, respiratory distress, T > 38°C, CRP > 50 or WCC > 15 × 109 /l as indications for CXR, to have a sensitivity of 88% (with 95% CI 0·78-0·95) and specificity of 46% (95% CI 0·43-0·50) for clinically significant findings.

Study of montelukast in children with sickle cell disease (SMILES): a study protocol for a randomised controlled trial.

BACKGROUND: Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA. METHODS: The Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3-7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry. DISCUSSION: Findings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA. TRIAL REGISTRATION: ClinicalTrials.gov NCT04351698 . Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020.

Biopsychosocial Predictors of Quality of Life in Paediatric Patients With Sickle Cell Disease.

Sickle cell disease (SCD) refers to a group of inherited blood disorders with considerable morbidity that causes severe pain, reduces life expectancy, and requires significant self-management. Acute painful episodes are the hallmark of SCD, but persistent daily pain is also highly prevalent in this population. Characterising the impact and experience of SCD-related morbidity (i.e., sleep disruption, frequent emergency department visits, cognitive dysfunction) on health-related quality of life (HRQOL) requires multiple assessment methods to best capture the underlying mechanisms. To gain a greater understanding of the effect of common symptom categories on HRQOL and to determine potential pain coping targets, the present study investigated whether demographic, socioeconomic, sleepiness, pain burden, frequency of emergency department (ED) visits, and cognition predicted HRQOL in a paediatric sample of patients with SCD. Our study was a secondary analysis of baseline assessment data of children with SCD aged 8-15 years (n = 30) in the Prevention of Morbidity in Sickle Cell Anaemia Phase 2b (POMSb2) randomised controlled clinical trial of auto-adjusting continuous positive airways pressure. Patients completed cognitive testing (IQ, Processing Speed Index, Delis-Kaplan Executive Function Scale (DKEFS) Tower, Conner's Continuous Performance Test), sleepiness (Epworth Sleepiness Scale), and HRQOL (PedsQL Sickle Cell Module) at baseline. Patients reported pain burden (Sickle Cell Pain Burden Inventory-Youth) each month over 8 visits. Caregivers provided demographic information and reported their child's executive function (Behavioural Rating Inventory of Executive Function) at baseline. Data from our analysis demonstrated that demographic factors (i.e., age, gender, level of neighbourhood deprivation) and treatment variables (i.e., hydroxyurea use) did not independently predict HRQOL, and laboratory values (i.e., haemoglobin, haematocrit, mean oxygen saturation) were not significantly correlated with HRQOL (ps > 0.05). However, sleepiness, pain burden, ED visits, and executive dysfunction independently predicted HRQOL (R 2 = 0.66) with large effects (η2 = 0.16 to 0.32). These findings identify specific, measurable symptom categories that may serve as targets to improve HRQOL that are responsive to change. This knowledge will be useful for multimodal interventions for paediatric patients with SCD that include sleep management, pain coping strategies, and executive function training.

Clinical management of sickle cell liver disease in children and young adults.

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.

Heterogeneity of respiratory disease in children and young adults with sickle cell disease.

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.

Ruxolitinib treatment in an infant with JAK2+ polycythaemia vera-associated Budd-Chiari syndrome.

Budd-Chiari syndrome (BCS) is caused by hepatic venous outflow obstruction commonly seen with myeloproliferative neoplasms (MPNs). Polycythaemia vera (PV) is a very rare MPN in childhood. This is the youngest reported patient diagnosed with PV and BCS secondary to JAK V617F mutation.A 26-month-old girl was admitted with a 5-month history of abdominal distension, hepatosplenomegaly and ascites. Imaging studies revealed occlusion of the right hepatic vein and marked attenuation of the middle and left hepatic veins. BCS was diagnosed after excluding other causes of chronic liver disease. Mandatory prothrombotic workup revealed underlying PV.Partial recanalisation of hepatic veins occurred following anticoagulation therapy and PV was well controlled by pegylated interferon and hydroxycarbamide until she developed nephrotic syndrome, likely secondary to pegylated interferon. Therefore, treatment was modified to ruxolitinib, a novel-JAK-2 inhibitor; the therapy has been effective for almost 20 months with a good response and has no side effects.

Primary Budd-Chiari Syndrome in Children: King's College Hospital Experience.

Primary Budd-Chiari syndrome is a rare cause of liver disease in children in the western world. Here we present a retrospective review of children with Primary Budd-Chiari syndrome presenting from January 2001 to November 2015 to our hospital. Seven children were identified. Their presentation was mostly chronic. All had predisposing factors for thrombosis and were started on anticoagulation. Radiological interventions (2 transjugular intrahepatic portosystemic shunts and 1 hepatic vein stenting), liver transplant and mesocaval shunt were done in 3, 2, and 1 patients, respectively; 1 child underwent bone marrow transplantation following transjugular intrahepatic portosystemic shunts and 1 child was managed only medically. After liver transplantation, one child died 3 years later as a result of subarachnoid haemorrhage, whereas others remain well at a median follow-up of 6 years. Despite high morbidity, the disease can have a good long-term outcome with a multidisciplinary approach.

Airway and alveolar nitric oxide production, lung function, and pulmonary blood flow in sickle cell disease.

BACKGROUND: Children with sickle cell disease (SCD) often have obstructive lung function abnormalities which could be due to asthma or increased pulmonary blood volume; it is important to determine the underlying mechanism to direct appropriate treatment. In asthmatics, exhaled nitric oxide (FeNO) is elevated. FeNO, 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. METHODS: Lung function, airway NO flux and alveolar NO production, and effective pulmonary blood flow were assessed in 18 SCD children and 18 ethnic and age-matched controls. RESULTS: The SCD children compared to the controls had a higher respiratory system resistance (P = 0.0008), alveolar NO production (P = 0.0224), and pulmonary blood flow (P < 0.0001), but not airway NO flux. There was no significant correlation between FeNO and respiratory system resistance in either group, but in the SCD children, there were correlations between alveolar NO production (P = 0.0006) and concentration (P < 0.0001) and pulmonary blood flow. CONCLUSION: 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.

Acute human parvovirus B19 infection and nephrotic syndrome in patients with sickle cell disease.

Acute Human Parvovirus B19 (HPV B19) infection is the major cause of transient red cell aplasia (TRCA) and acute anaemia in patients with sickle cell disease (SCD). We report three cases of patients who developed nephrotic syndrome (NS) with chronic sequelae after initially presenting with HPV B19-associated TRCA. There was no correlation between evidence of HPV B19 infection and impaired renal function in our cohort of adult sickle cell patients. This is consistent with a view that although NS is potentially a rare complication of symptomatic acute HPV B19 infection, exposure to HPV B19 is not associated with an increased risk of renal disease.

Successful treatment of mixed-type autoimmune hemolytic anemia with rituximab in a child following liver transplantation.

Development of a severe form of mixed-type AIHA after orthotopic liver transplantation is a rare, but a life-threatening event. We report a case of mixed-type AIHA that developed in a child after hepatocyte and living-related orthotopic liver transplantation for factor VII deficiency.

Stroke prevention in the young child with sickle cell anaemia.

Cerebrovascular disease resulting in stroke is a serious and preventable complication of sickle cell anaemia (SCA). Children at high risk of preventable stroke can be identified by transcranial Doppler ultrasound (TCD). Current guidelines in the UK recommend annual TCD screening from 3 years, although studies suggest an earlier peak incidence, between 2 and 5 years. A single centre retrospective review was undertaken to identify the prevalence of stroke and success of TCD screening in young children. We report five episodes of stroke in under 3s and outcome of TCD screening in children under 3, compared to over 3. TCD analysis was as successful in the 2-3-year age group as in the 3-4-year group. We therefore propose that all children with SCA should be offered TCD screening from the age of 2 years. Furthermore, infants with high risk features of SCA should undergo a first attempt at TCD screening even earlier.

The effects of air quality on haematological and clinical parameters in children with sickle cell anaemia.

Sickle cell anaemia (SCA; HbSS) is characterised by its clinical variability, which is only partly explained by known genetic factors. Environmental factors are known to contribute to acute problems but their importance in chronic complications has not been analysed. We have studied 93 children with SCA in a single institution, who underwent transcranial Doppler scanning and steady-state blood tests in 2006. These data were correlated with each individual's exposure to pollution from dust (PM(10)), nitric oxide (NO) and nitrogen dioxide (NO(2)). This exposure was derived from patient postcodes and detailed street-level maps of average pollutant levels in 2006. All the pollutants correlated closely with each other. Increased exposure to pollution correlated with a significant reduction in total bilirubin levels, with a trend towards lower levels of lactate dehydrogenase and aspartate transaminase. There was significant correlation between extracranial internal carotid artery blood velocity and PM(10) exposure. These studies suggest that chronic exposure to air pollutants could explain some variability in SCA. The lower levels of bilirubin and other markers of haemolysis with increased exposure to air pollutants could be mediated by increased exposure to NO.

The presence of alpha-thalassaemia trait blunts the response to hydroxycarbamide in patients with sickle cell disease.

Hydroxycarbamide (HC), although a key drug therapy in sickle cell disease (SCD), does not result in a clinical response in all patients. Increases in fetal haemoglobin (HbF) and mean corpuscular volume of erythrocytes are standard clinical measures of HC efficacy in SCD. Genetic studies have determined that the majority of HbF regulation occurs outside the beta-globin locus. Approximately 30% of SCD patients have co-inherited alpha-thalassaemia resulting in hypochromic and microcytic erythrocytes. We provide data from 30 SCD patients (10 with alpha-thalassaemia) demonstrating that co-existing alpha-thalassaemia significantly affects several standard measures of HC efficacy in SCD.

A simple index using age, hemoglobin, and aspartate transaminase predicts increased intracerebral blood velocity as measured by transcranial Doppler scanning in children with sickle cell anemia.

OBJECTIVE: Increased intracerebral blood velocity measured by transcranial Doppler scanning identifies children with sickle cell anemia who are at increased risk of stroke. We have tried to develop an index based on routine clinical measurements that also predicts increased intracerebral blood flow. METHOD: Routinely collected clinical and laboratory data were correlated with transcranial Doppler measurements on children with sickle cell anemia seen in a single institution in 2006. The index produced was validated on a second independent data set from children with sickle cell anemia. RESULTS: The time-averaged mean of the maximum velocity in centimeters per second in the middle cerebral artery circulation correlated significantly with age, hemoglobin, lactate dehydrogenase, and aspartate transaminase levels, white blood cell count, and creatinine level. On multiple regression, hemoglobin and aspartate transaminase levels maintained their significance, whereas age had borderline significance, and an index was developed linked to a time-averaged mean of the maximum velocity of 220 - (8 x hemoglobin) - (1.4 x age) + (0.4 x aspartate transaminase). This detected a time-averaged mean of the maximum velocity of >170 cm/second with 100% sensitivity and 58% specificity. The index was validated on the second data set and again showed 100% sensitivity with 73% specificity. CONCLUSION: This simple index has the potential to identify children who are at higher risk of cerebrovascular disease to allow them to be prioritized for transcranial Doppler scanning and other intracerebral imaging.

Transcranial Doppler scanning and the assessment of stroke risk in children with HbSC [corrected] disease.

OBJECTIVE: To assess the role of transcranial Doppler (TCD) scanning in assessing the risk of stroke in children with haemoglobin SC (HbSC) disease. TCD scanning has an established role in primary stroke prevention in sickle cell anaemia 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, UK. PATIENTS: 46 children with HbSC disease who have undergone 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 94 cm/s, with a 98(th) centile of 128 cm/s. This is significantly less than the published ranges for HbSS, with a mean reading of 129 cm/s. One child had a stroke at the age of 5 years, when her TAMMV was measured at 146 cm/s. CONCLUSIONS: Further studies are needed to assess stroke risk in HbSC disease, but we suggest that TCD measurements are potentially useful in this condition, and that readings greater than 128 cm/s are abnormally high and warrant further investigation.

Lamin B-receptor mutations in Pelger-Huët anomaly.

Pelger-Huët anomaly is an inherited abnormality of neutrophils, characterized by reduced nuclear segmentation and an apparently looser chromatin structure. Following linkage studies in two families, the lamin B-receptor (LBR) was sequenced and mutations found: CCG-->CTG causing proline-->leucine in codon 119 of exon 3, and IVS11-9 A-->G, disrupting the splice acceptor site. The LBR gene (LBR) was also sequenced from a single English man with Pelger-Huët anomaly and a heterozygous C-->G mutation was found in codon 569 of exon 14, predicted to cause a proline-->arginine. Our results confirm recently published findings that LBR mutations cause Pelger-Huët.