Susan E. Height

Windy weather and low humidity are associated with an increased number of hospital admissions for acute pain and sickle cell disease in an urban environment with a maritime temperate climate

Sickle cell disease (SCD) is characterised by intermittent episodes of acute severe pain, related to vaso‐occlusion. Environmental factors are thought to play an important role, and studies in tropical countries have suggested that cold and rainy seasons are associated with increased episodes of acute pain. We have studied retrospectively the number of admissions with acute pain and SCD to Kings College Hospital, London, together with daily meteorological records collected locally. Data from 1400u2003d and 1047 separate admissions were analysed. Increased admissions were significantly associated with increased wind speed and low humidity, but showed no relationship to temperature, rainfall or barometric pressure. The strongest effect was for (maximum wind speed)/humidity, with 464 admissions on days in the lowest two quartiles of this parameter and 582 in the highest quartiles. The effect of high wind and low humidity is likely to be related to skin cooling.

Lamin B‐receptor mutations in Pelger–Huët anomaly

Summary. Pelger–Huët anomaly is an inherited abnormality of neutrophils, characterized by reduced nuclear segementation 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.

Auto-adjusting positive airway pressure in children with sickle cell anemia: results of a phase I randomized controlled trial

Sleep related breathing disorders and especially low nocturnal oxygen saturation may favor complications of sickle cell disease (SCD) In this phase I trial, autoadjusting continuous positive airway pressure (CPAP) was shown to be a feasible and safe therapy for SCD children. Sleep breathing disorders were improved, and there was evidence of a trend towards reduction of diurnal pain. Low nocturnal oxygen saturation (SpO2) is implicated in complications of Sickle Cell Anemia (SCA). Twenty-four children with SCA were randomized to receive overnight auto-adjusting continuous positive airway pressure (auto-CPAP) with supplemental oxygen, if required, to maintain SpO2 ≥94% or as controls. We assessed adherence, safety, sleep parameters, cognition and pain. Twelve participants randomized to auto-CPAP (3 with oxygen) showed improvement in Apnea/Hypopnea Index (p<0.001), average desaturation events >3%/hour (p=0.02), mean nocturnal SpO2 (p=0.02) and cognition. Primary efficacy endpoint (Processing Speed Index) showed no group differences (p=0.67), but a second measure of processing speed and attention (Cancellation) improved in those receiving treatment (p=0.01). No bone marrow suppression, rebound pain or serious adverse event resulting from auto-CPAP use was observed. Six weeks of auto-CPAP therapy is feasible and safe in children with SCA, significantly improving sleep-related breathing disorders and at least one aspect of cognition.

Serum lactate dehydrogenase activity as a biomarker in children with sickle cell disease

Serum lactate dehydrogenase (LDH) levels were studied in children with HbSS and HbSC in a single institution, and their relationship to cerebral vasculopathy as assessed by transcranial Doppler scanning (TCD). All children with HbSS (nu2003=u200397) and HbSC (nu2003=u200318) who underwent a TCD scan in 2006 were studied. LDH levels were higher in HbSS patients than HbSC (581u2003IU/l vs. 305u2003IU/l, Pu2003<u20030·001). In children with HbSS, LDH correlated significantly with haemoglobin, reticulocytes, aspartate transaminase and creatinine. LDH also correlated positively and significantly with TCD measurements in the middle and anterior cerebral artery circulations in the children with HbSS.

Extracranial internal carotid arterial disease in children with sickle cell anemia

Background Sickle cell anemia is one of the commonest causes of stroke in children. It is usually, but not always, associated with intracranial vasculopathy. We have assessed the value of ultrasound screening for extracranial internal carotid artery disease. Design and Methods Using Doppler ultrasound scanning, we assessed peak systolic blood velocity, tortuosity and stenosis in the extracranial internal carotid arteries of 236 children with sickle cell anemia. Seventeen of the children had previously had a stroke. All measurements were performed as part of routine clinical care. Results The median extracranial internal carotid artery velocity was 148cm/s (5th centile 84, 95th centile 236). Higher velocities were significantly correlated with younger age, higher white blood cell counts and higher rates of hemolysis. Fourteen (5.9%) had tortuous extracranial internal carotid arteries and 13 (5.4%) had stenosis or occlusion. None of the children with tortuous vessels but 8 of those with stenosis had previously had a stroke; the presence of stenosis was strongly associated with overt clinical stroke (OR 35.9, 95% C.I. 9.77–132, P<0.001). In 6 children, extracranial stenosis was part of extensive intracranial vasculopathy, but in 2 there was no evidence of intracranial disease. Stenosis seemed to be more common in older children. Conclusions Extracranial internal carotid artery stenosis is strongly associated with stroke in children with sickle cell anemia, and may explain some cases of stroke without overt intracranial vasculopathy. Doppler ultrasound scanning of extracranial internal carotid arteries is non-invasive and fairly quick to perform and may identify children at increased risk of stroke who would otherwise be missed. The value of extracranial internal carotid artery scanning should be studied prospectively.

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 × hemoglobin) − (1.4 × age) + (0.4 × 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.

The associations between air quality and the number of hospital admissions for acute pain and sickle-cell disease in an urban environment.

The clinical severity of sickle‐cell disease (SCD) is dependent on genetic and environmental variables. Environmental factors have been poorly studied. We have investigated possible links between air pollution and acute pain in SCD. We retrospectively studied the numbers of daily admissions with acute sickle‐cell pain to Kings College Hospital, London, in relation to local daily air quality measurements. We analysed 1047 admissions over 1400u2003d (1st January 1998–31st October 2001). Time series analysis was performed using the cross‐correlation function (CCF). CCF showed a significant association between increased numbers of admissions and low levels of nitric oxide (NO), low levels of carbon monoxide (CO) and high levels of ozone (O3). There was no association with sulphur dioxide (SO2), nitrogen dioxide or PM10 (dust). The significant results were further examined using quartile analysis. This confirmed that high levels of O3 and low levels of CO were associated with increased numbers of hospital admissions. Low NO levels were also associated with increased admissions but did not reach statistical significance on quartile analysis. Our study suggests air quality has a significant effect on acute pain in SCD and that patients should be counselled accordingly. The potential beneficial effect of CO and NO is intriguing and requires further investigation.

Transcranial Doppler scanning and the assessment of stroke risk in children with haemoglobin sickle cell 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 98th 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.

The presence of α-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 β‐globin locus. Approximately 30% of SCD patients have co‐inherited α‐thalassaemia resulting in hypochromic and microcytic erythrocytes. We provide data from 30 SCD patients (10 with α‐thalassaemia) demonstrating that co‐existing α‐thalassaemia significantly affects several standard measures of HC efficacy in SCD.

Heterogeneity of the ɛγδβ-thalassaemias: characterization of three novel English deletions

We have characterized three novel ɛγδβ‐thalassaemia deletions in three English families. Two of the deletions, 114 and 439u2003kb, removed the entire β‐globin gene complex, including a variable number of flanking olfactory receptor (HOR) genes. The 98‐kb deletion extended 90‐kb upstream of the ɛ gene to 8u2003kb upstream of the Gγ‐gene, leaving the γ,δ and β‐genes intact. The 439u2003kb deletion is the largest deletion reported so far to cause ɛγδβ‐thalassaemia; heterozygotes for this deletion were variably affected by neonatal haemolytic anaemia. Two of the deletions were de novo. Breakpoints of all three deletions occurred within regions of L1 or Alu repeats and contained short regions of direct homology between the flanking sequences, a feature that is likely to have contributed to the illegitimate recombinations.