Search

Introduction: Anemia in children is a major public health problem throughout the world. It is often multifactorial, iron deficiency being the most frequent etiology. Consequences are diverse and largely under evaluated. Areas covered: This paper briefly reviews the main causes and focus on the potential consequences of acute and chronic anemia in children. Expert commentary: Anemia in children should never be trivialized. Even if iron deficiency is frequently involved, other potentially life-threatening causes are possible and should be looked for. The exact contribution of anemia to child mortality and morbidity is difficult to assess because of overlapping comorbidities. Chronic anemia may impair growth, cardiac function and cognitive development in infants but other consequences are rather poorly described and should be explored more thoroughly.

Importance: Temporal macular involvement in sickle cell disease can now easily be detected by optical coherence tomography (OCT). However, while recent studies have demonstrated its high prevalence, little is known about its potential consequences on visual function., Objective: To assess the visual function of patients with sickle cell disease with no visual symptoms despite temporal macular atrophy., Design, Setting, and Participants: This retrospective case series included data collection and explorations made in a single referral center for sickle cell disease in 2016. Three patients with sickle cell disease exhibiting preserved visual acuity but showing temporal macular retinal atrophy were included., Exposures: Patients underwent the following explorations: best-corrected distance and near visual acuity evaluation; dilated fundus examination; OCT with 12 × 6-mm thickness map; horizontal, vertical, and en face sections; OCT angiography of the 6 × 6-mm perifoveal retina; 30° and 12° central visual fields; Lanthony 15-hue color vision test; automated static contrast sensitivity test; and global electroretinography., Main Outcomes and Measures: The OCT thickness maps were checked for areas of retinal thinning, appearing as blue patches. When present, these areas were compared with the areas of superficial and deep capillary flow loss on OCT angiography and with the scotomas on visual fields. Contrast sensitivity and color vision loss were quantified., Results: All 3 patients included had homozygous sickle cell disease. They presented with a 20/20 distance visual acuity, and Parinaud 1,5 near visual acuity in both eyes. They were all followed up for a severe cerebral vasculopathy related to sickle cell disease. The areas of atrophy involved the inner retinal layers and were associated with an absence of signal in the deep capillary plexuses in OCT angiography. These patches of retinal thinning were also matching with scotomas in the automated visual fields. Color vision ability and contrast sensitivity were impaired in all patients. Global electroretinography findings were normal., Conclusions and Relevance: Temporal macular atrophy in sickle cell disease may have direct consequences on visual function, including in children, even when visual acuity is preserved. Optical coherence tomographic imaging may be warranted when evaluating patients with sickle cell disease, even if asymptomatic with 20/20 visual acuity.

Although the primary origin of sickle cell disease is a hemoglobin disorder, many types of cells contribute considerably to the pathophysiology of the disease. The adhesion of neutrophils to activated endothelium is critical in the pathophysiology of sickle cell disease and targeting neutrophils and their interactions with endothelium represents an important opportunity for the development of new therapeutics. We focused on endothelin-1, a mediator involved in neutrophil activation and recruitment in tissues, and investigated the involvement of the endothelin receptors in the interaction of neutrophils with endothelial cells. We used fluorescence intravital microscopy analyses of the microcirculation in sickle mice and quantitative microfluidic fluorescence microscopy of human blood. Both experiments on the mouse model and patients indicate that blocking endothelin receptors, particularly ET B receptor, strongly influences neutrophil recruitment under inflammatory conditions in sickle cell disease. We show that human neutrophils have functional ET B receptors with calcium signaling capability, leading to increased adhesion to the endothelium through effects on both endothelial cells and neutrophils. Intact ET B function was found to be required for tumor necrosis factor α-dependent upregulation of CD11b on neutrophils. Furthermore, we confirmed that human neutrophils synthesize endothelin-1, which may be involved in autocrine and paracrine pathophysiological actions. Thus, the endothelin-ET B axis should be considered as a cytokine-like potent pro-inflammatory pathway in sickle cell disease. Blockade of endothelin receptors, including ET B , may provide major benefits for preventing or treating vaso-occlusive crises in sickle cell patients., (Copyright© 2017 Ferrata Storti Foundation.)

Tuberculosis (TB) and sickle cell anaemia (SCA) may affect the same population of patients, particularly in Africa but also in high-TB incidence areas in developed countries. However, few data are available from children with SCA who develop TB. The aim of this study was to describe the clinical features and outcome of TB diagnosed in children with SCA. We conducted a retrospective, descriptive study in three referral centre of Sickle Cell Disease in Paris, France. We included 11 patients with SCA who develop TB. The median age at TB diagnosis was 11 years [7.5-14.5]. Two patients were asymptomatic and nine patients were symptomatic. Six patients had pulmonary TB (pulmonary, pleural and mediastinal lesions). Five patients had extrapulmonary TB (osteoarticular TB, hepatic TB, cervical and mediastinal TB). Mycobacterium tuberculosis was isolated in four of the 11 cases. All patients recovered after a median of 6 months of anti-TB treatment. The localisation of TB and outcome after treatment in our SCA patients were similar to the one observed in an age-and sex-matched control group of non-SCA patient with TB., Conclusion: despite the low number of patients included in our study, SCA does not seem to be a risk factor for severe TB. What is Known: • Tuberculosis (TB) remains a global health problem particularly in developing countries, and Sickle cell anaemia (SCA) is currently one of the most common genetic diseases in the world that mainly affects African populations. • Very few data are available on TB in SCA patients. What is New: • The features of TB in children with SCA seem to be comparable to those expected in general population, with favourable outcomes in response to standard treatment. • Monitoring the dosage of anti-TB treatments could be of interest because of the possible impact of SCA on drug metabolism.

Background: Multiple burr hole (MBH) surgery is a simple, safe, and effective indirect technique of revascularization in moyamoya angiopathy (MM). However, it is not yet recognized as a first-line treatment., Objective: To assess the long-term outcome and perioperative complications in a large single-center cohort of children with MM who underwent burr hole surgery., Methods: This study is a retrospective analysis of children who underwent surgery for MM in a national reference center for pediatric stroke between 1999 and 2015. Sixty-four children (108 hemispheres, median age 7 years) were consecutively treated. The indication for revascularization was previous stroke or transient ischemic attack (TIA) or rapidly progressive disease on brain magnetic resonance imaging (MRI) and digital subtraction angiography. Children were followed with clinical examinations, telephone interviews, and MRI with any clinical recurrence of stroke or TIA used as the primary endpoint. Surgical mortality and morbidity were documented., Results: Sixty-four patients were operated (bilateral MBH n = 39, unilateral procedure n = 25). At a mean follow-up of 4.2 years and 270.6 patient years, 89.1% of patients had not suffered any recurrent stroke or TIA. A second surgery was required in 5 cases after unilateral revascularization, and in 3 cases after bilateral MBH. Mortality associated with the procedure was 0. Postoperative Matsushima angiographic grading was the only predictive factor of ischemic recurrence ( P = .036)., Conclusion: In pediatric MM, MBH compares favorably to other indirect or direct revascularization techniques in children in the prevention of stroke or TIA., (Copyright © 2017 by the Congress of Neurological Surgeons)

Patients with sickle cell disease (SCD) show a high prevalence of red blood cell (RBC) alloimmunization, but few studies have focused on children. We aimed to study the prevalence and risk factors of RBC alloimmunization in SCD children. We retrospectively analysed the medical and transfusion files for 245 SCD children hospitalized in our centre in 2014 and included 175 patients who had received at least one RBC unit in their lifetime. The main clinical and immuno-haematological characteristics of alloimmunized and non-alloimmunized patients were compared. The prevalence of alloimmunization was 13·7% [95% confidence interval (CI) (8·6-18·6)], and 7·4% [95% CI (3·5-11·3)] after excluding the probable irregular natural antibodies (anti-M, anti-Le a , anti-Le b , anti-Le x ). Main risk factors for alloimmunization were increased number of RBC units received (median of 65 vs. 10 units per patient; P = 0·01) and the presence of one or more red cell autoantibodies (46·2% vs. 4·7%; P < 0·0001). The alloimmunization rate was higher for episodically transfused than chronically transfused patients (1·43 vs. 0·24/100 units received; P < 0·001). The presence of red cell autoantibodies appears to be a major risk factor for alloimmunization in SCD children and could justify specific transfusion guidelines., (© 2017 John Wiley & Sons Ltd.)

Sickle cell disease is an increasing global health burden. This inherited disease is characterized by a remarkable phenotypic heterogeneity, which can only partly be explained by genetic factors. Environmental factors are likely to play an important role but studies of their impact on disease severity are limited and their results are often inconsistent. This study investigated associations between a range of environmental factors and hospital admissions of young patients with sickle cell disease in London and in Paris between 2008 and 2012. Specific analyses were conducted for subgroups of patients with different genotypes and for the main reasons for admissions. Generalized additive models and distributed lag non-linear models were used to assess the magnitude of the associations and to calculate relative risks. Some environmental factors significantly influence the numbers of hospital admissions of children with sickle cell disease, although the associations identified are complicated. Our study suggests that meteorological factors are more likely to be associated with hospital admissions for sickle cell disease than air pollutants. It confirms previous reports of risks associated with wind speed (risk ratio: 1.06/standard deviation; 95% confidence interval: 1.00-1.12) and also with rainfall (1.06/standard deviation; 95% confidence interval: 1.01-1.12). Maximum atmospheric pressure was found to be a protective factor (0.93/standard deviation; 95% confidence interval: 0.88-0.99). Weak or no associations were found with temperature. Divergent associations were identified for different genotypes or reasons for admissions, which could partly explain the lack of consistency in earlier studies. Advice to patients with sickle cell disease usually includes avoiding a range of environmental conditions that are believed to trigger acute complications, including extreme temperatures and high altitudes. Scientific evidence to support such advice is limited and sometimes confusing. This study shows that environmental factors do explain some of the variations in rates of admission to hospital with acute symptoms in sickle cell disease, but the associations are complex, and likely to be specific to different environments and the individual's exposure to them. Furthermore, this study highlights the need for prospective studies with large numbers of patients and standardized protocols across Europe., (Copyright© Ferrata Storti Foundation.)

The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS). In patients with sickle cell anemia (SCA), iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*<20 ms, in patients with thalassemia, SCA, or MDS. Patient inclusion criteria were an accurate record of erythrocyte concentrates (ECs) received, a transfusion history >8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15%) patients with thalassemia, none with SCA, and 4 (16%) with MDS. The liver iron content (LIC) ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29). Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P<0.001). Hepcidin was low in thalassemia, normal in SCA, and markedly elevated in MDS (P<0.001). Two mechanisms may explain that iron deposition largely spares the heart in SCA: the high level of erythropoiesis recycles the iron and the chronic inflammation retains iron within the macrophages. Thalassemia, in contrast, is characterized by inefficient erythropoiesis, unable to handle free iron. Iron accumulation varies widely in MDS syndromes due to the competing influences of abnormal erythropoiesis, excess iron supply, and inflammation.

Introduction  Splenectomy in children is nowadays widely performed by laparoscopy, the major risk being operative hemorrhage. We hereby compare the results of two different techniques of vascular control. Materials and Methods  We retrospectively reviewed all patients undergoing a laparoscopic splenectomy (LS) for hematologic disease at a single institution from 2004 to 2013. LS was performed by a lateral approach. The 10-mm optic port was placed in the umbilicus and two 5-mm working ports were placed in the left lower quadrant and in the right upper quadrant near the midline.An additional port was added in the epigastrium if needed. The classic technique (CT) consisted in the separate sealing and section of the splenic artery and vein above the pancreas tail. The modified technique (MT) consisted in the dissection of each segmental splenic vessel, at the lower, middle, and upper parts of the spleen. They were then divided without individualizing the artery from the vein. Results  Total 69 patients were operated on at a mean age of 7.8 ± 0.6 years, 30 by CT and 39 by MT. In 20 patients (6 CT, 14 MT) a cholecystectomy was associated. The operative time, length of hospitalization, and number of postoperative complications for CT/MT were respectively 139/117 mn ( p  = 0.04), 3.8/3.0 days ( p  = 0.01), 12/3 ( p  = 0.002). An additional port was less needed with MT ( p  = 0.03). Conclusions  The joint sealing of segmental splenic artery and vein appeared safe, efficient and quicker for LS, with no increased risk of operative bleeding and postoperative complications., (Georg Thieme Verlag KG Stuttgart · New York.)

Iron overload is an ineluctable complication in chronically transfused children warranting accurate assessment to avoid related morbidity. We investigated longitudinally the relationships between ferritin levels and hepatic and cardiac T2* magnetic resonance imaging (MRI) in a cohort of chronically transfused children receiving chelation therapy. Thirty children with sickle cell anemia (SCA) and 7 with thalassemia major (TM) chelated similarly by deferasirox were analyzed. Sex ratio, age, median duration of transfusion programs (5 y; range, 2 to 14 y), median transfusion iron intake 0.54 mg/kg/d (range, 0.27 to 0.74 mg/kg/d), and median ferritin level (1550 mg/L; range, 184 to 6204 mg/L) were comparable in TM and SCA. A significant relation was found between ferritin level and transfusion iron intake (P<0.001) despite chelation therapy. Analysis of 73 hepatic T2* MRI performed yearly demonstrated severe hepatic iron overload (≥14 mg/g) in 38.3% cases and a strong relationship between serum ferritin level and liver iron content both in SCA and TM (P<0.001). Analysis of 55 cardiac T2* MRI measurements found no cardiac overload in patients with SCA. Cardiac iron overload was moderate in 4 cases and severe in 1 case of TM. In almost half the cases, ferritin trend correctly predicted hepatic iron trend, both in patients with SCA and TM but failed to predict cardiac iron trend, notably in TM patients. Despite chelation therapy, iron burden in chronically transfused patients remains a threat. Ferritin levels are associated with liver iron overload in chelated children with SCA and TM, but iron burden should be best monitored with MRI whenever the setting allows it.

Background: Sickle-cell trait (HbAS) reduces falciparum malaria risk and suppresses parasitaemia. Although several candidate mechanisms have been proposed, their epidemiological, clinical and experimental correlates have not been adequately explained. To explore the basis for generally lower parasitaemias and delayed malaria episodes in children with HbAS, it is hypothesized here that their spleen-dependent removal of ring-infected red blood cells (RBCs) is more efficient than in children with normal haemoglobin A (HbAA)., Methods: The mechanical splenic retention of Plasmodium falciparum-infected RBCs from subjects with HbAS or HbAA was investigated using two physiologically relevant methods: microsphiltration and ex vivo spleen perfusion. P. falciparum-infected RBCs obtained from in vitro cultures and from patients were used in either normoxic or hypoxic conditions. The effect of sickling in ring-infected HbAS RBCs was also investigated., Results: When a laboratory-adapted parasite strain was analysed, ring-infected HbAA RBCs were retained in microsphilters at similar or greater levels than ring-infected HbAS RBCs, under normoxic (retention rate 62.5 vs 43.8 %, P < 0.01) and hypoxic (54.0 vs 38.0 %, P = 0.11) conditions. When parasitized RBCs from Malian children were analysed, retention of ring-infected HbAA and HbAS RBCs was similar when tested either directly ex vivo (32.1 vs 28.7 %, P = 0.52) or after one re-invasion in vitro (55.9 vs 43.7 %, P = 0.30). In hypoxia, sickling of uninfected and ring-infected HbAS RBCs (8.6 vs 5.7 %, P = 0.51), and retention of ring-infected HbAA and HbAS RBCs in microsphilters (72.5 vs 68.8 %, P = 0.38) and spleens (41.2 vs 30.4 %, P = 0.11), also did not differ. Retention of HbAS and HbAA RBCs infected with mature P. falciparum stages was greater than 95 %., Conclusions: Sickle-cell trait is not associated with higher retention or sickling of ring-infected RBCs in experimental systems reflecting the mechanical sensing of RBCs by the human spleen. As observed with HbAA RBCs, HbAS RBCs infected with mature parasites are completely retained. Because the cytoadherence of HbAS RBCs infected with mature parasites is impaired, the very efficient splenic retention of such non-adherent infected RBCs is expected to result in a slower rise of P. falciparum parasitaemia in sickle-cell trait carriers.

We conducted a retrospective study on newborns with sickle-cell disease (SCD), born 1995-2009, followed in a multicentre hospital-based network. We assessed patient outcomes, medical care and compliance with the national guidelines published in December 2005. Data from 1033 patients (742 SS/Sβ°-thalassaemia) with 6776 patient-years of follow-up were analysed (mean age 7·1 ± 3·9 years). SCD-related deaths (n = 13) occurred only in SS-genotype patients at a median age of 23·1 months, mainly due to acute anaemia (n = 5, including 2 acute splenic sequestrations) and infection (n = 3). Treatment non-compliance was associated with a 10-fold higher risk of SCD-related death (P = 0·01). Therapeutic intensification was provided for all stroke patients (n = 12), almost all patients with abnormal transcranial Doppler (TCD) (n = 76) or with >1 acute chest syndrome/lifetime (n = 64) and/or ≥3 severe vaso-occlusive crises/year (n = 100). Only 2/3 of patients with baseline haemoglobin <70 g/l received intensification, mainly for other severity criteria. Overall, hydroxycarbamide was under-prescribed, given to 2/3 of severe vaso-occlusive patients and 1/3 of severely anaemic patients. Nevertheless, introduction of the on-line guidelines was concomitant with an improvement in medical care in the 2006-2009 cohort with a trend towards increased survival at 5 years, from 98·3% to 99·2%, significantly increased TCD coverage (P = 0·004) and earlier initiation of intensification of therapy (P ≤ 0·01)., (© 2016 John Wiley & Sons Ltd.)

The aim of this study was to describe the clinical and biological features of Mevalonate kinase deficiency (MKD) in patients diagnosed in adulthood. This is a French and Belgian observational retrospective study from 2000 to 2014. To constitute the cohort, we cross-check the genetic and biochemical databases. The clinical, enzymatic, and genetic data were gathered from medical records. Twenty-three patients were analyzed. The mean age at diagnosis was 40 years, with a mean age at onset of symptoms of 3 years. All symptomatic patients had fever. Febrile attacks were mostly associated with arthralgia (90.9%); lymphadenopathy, abdominal pain, and skin lesions (86.4%); pharyngitis (63.6%); cough (59.1%); diarrhea, and hepatosplenomegaly (50.0%). Seven patients had psychiatric symptoms (31.8%). One patient developed recurrent seizures. Three patients experienced renal involvement (13.6%). Two patients had angiomyolipoma (9.1%). All but one tested patients had elevated serum immunoglobulin (Ig) D level. Twenty-one patients had genetic diagnosis; most of them were compound heterozygote (76.2%). p.Val377Ile was the most prevalent mutation. Structural articular damages and systemic AA amyloidosis were the 2 most serious complications. More than 65% of patients displayed decrease in severity and frequency of attacks with increasing age, but only 35% achieved remission. MKD diagnosed in adulthood shared clinical and genetic features with classical pediatric disease. An elevated IgD concentration is a good marker for MKD in adults. Despite a decrease of severity and frequency of attacks with age, only one-third of patients achieved spontaneous remission.

Sickle cell disease induces specific brain alterations that involve both the macrocirculation and the microcirculation. The main overt neurovascular complications in children are infarctive stroke, transient ischaemic attack and cerebral haemorrhage. Silent cerebral infarction, cognitive dysfunction and recurrent headache are also common. Cerebrovascular disease selectively affects children with the HbSS or HbS-β(0) genotypes (i.e. sickle cell anaemia). The incidence of stroke peaks between 2 and 5 years of age (1·02/100 patient-years) and increases with the severity of the anaemia. Most strokes can be prevented by annual transcranial Doppler screening from 2 to 16 years of age and providing chronic blood transfusion when this investigation shows elevated blood-flow velocities. The role for hydroxycarbamide in children with abnormal transcranial Doppler findings is under investigation. After a stroke, chronic blood transfusion is very strongly recommended, unless haematopoietic stem cell transplantation can be performed. Routine magnetic resonance imaging shows that more than one-third of children have silent cerebral infarction, which is associated with cognitive impairments. Screening for silent infarcts seems legitimate, since their presence may lead to supportive treatments. The role for more aggressive interventions such as hydroxycarbamide or chronic blood transfusion is debated., (© 2015 John Wiley & Sons Ltd.)

Red blood cells (RBCs) are deformable and flow through vessels narrower than their own size. Their deformability is most stringently challenged when they cross micrometer-wide slits in the spleen. In several inherited or acquired RBC disorders, blockade of small vessels by stiff RBCs can trigger organ damage, but a functional spleen is expected to clear these abnormal RBCs from the circulation before they induce such complications. We analyzed flow behavior of RBCs in a microfluidic chip that replicates the mechanical constraints imposed on RBCs as they cross the human spleen. Polymer microchannels obtained by soft lithography with a hydraulic diameter of 25 μm drove flow into mechanical filtering units where RBCs flew either slowly through 5- to 2-μm-wide slits or rapidly along 10-μm-wide channels, these parallel paths mimicking the splenic microcirculation. Stiff heated RBCs accumulated in narrow slits seven times more frequently than normal RBCs infused simultaneously. Stage-dependent retention of Plasmodium falciparum-infected RBCs was also observed in these slits. We also analyzed RBCs from patients with hereditary spherocytosis and observed retention for those having the most altered mechanical properties as determined by ektacytometry. Thus, in keeping with previous observations in vivo and ex vivo, the chip successfully discriminated poorly deformable RBCs based on their distinct mechanical properties and on the intensity of the cell alteration. Applications to the exploration of the pathogenesis of malaria, hereditary spherocytosis, sickle cell disease and other RBC disorders are envisioned., (© 2015 Wiley Periodicals, Inc.)

Aim: To address risk of first or recurrent cerebral haemorrhage in children with sickle-cell disease (SCD) who are being managed with modern stroke prevention strategies., Method: A systematically followed SCD paediatric cohort was retrospectively studied over a 9-year period. Haemorrhagic risk was defined as intracranial haemorrhage occurrence or intracranial aneurysm diagnosis during the study period. Ischaemic risk was defined as cerebrovascular ischaemic event occurrence or transcranial Doppler/magnetic resonance imaging hallmarks of ischaemic risk finding during the study period., Results: Among the 251 patients in the cohort, 36 patients were included in the ischaemic group. Seven patients were included in the haemorrhagic group, of which five also met the criteria for the ischaemic group. Age at first haemorrhagic symptom/hallmark of risk was older (10.4 vs 6.2 years old, p=0.036). Nine intracranial saccular aneurysms were found, mostly on the posterior circulation. Two patients had endovascular embolization., Interpretation: The ratio of ischaemic to haemorrhagic risk was not modified with modern management compared with historical series. Intracranial aneurysm in children with SCD had specific characteristics, close to intracranial aneurysms described in adults with SCD. Data favoured concurrent development of intracranial SCD-associated anterior stenosis and posterior dilation, suggesting common pathophysiology and management strategies., (© 2014 Mac Keith Press.)

Sickle cell anaemia (SCA) results from a single mutation in the β globin gene. It is seldom symptomatic in the first semester of life. We analysed the expression pattern of 9 adhesion molecules on red blood cells, in a cohort of 54 SCA and 17 non-SCA very young infants of comparable age (median 144 days, 81-196). Haemoglobin F (HbF) level was unsurprisingly elevated in SCA infants (41.2% ± 11.2) and 2-4 fold higher than in non-SCA infants, yet SCA infants presented significantly decreased Hb level and increased reticulocytosis. Cytometry analysis evidenced a specific expression profile on reticulocytes of SCA infants, with notably an increased expression of the adhesion molecules Lu/BCAM, ICAM-4 and LFA-3, both in percentage of positive cells and in surface density. No significant difference was found on mature red cells. Our findings demonstrate the very early onset of reticulocyte membrane modifications in SCA asymptomatic infants and allow an insight into the first pathological changes with the release of stress reticulocytes expressing a distinctive profile of adhesion molecules.

Acute complications in sickle cell disease are a major and life-long cause for hospital referral. The most frequent events are painful acute vaso-occlusive crisis involving the limbs and back, and acute chest syndrome. Acute vaso-occlusive crisis is a therapeutic emergency because of the very high level of pain. Acute chest syndrome may be potentially fatal and must be adequately searched for and treated. Sickle cell patients are susceptible to pneumococcal infections notably, but any infection may favour vaso-occlusive crisis. Triggers of sickle cell vase occlusion must be tracked and corrected, if possible. Moderate crisis can be managed at home, but referral is necessary as soon as opiates are needed and/or if acute chest syndrome is suspected. Additional treatments besides opiates include co analgesics, oxygen, hydration, physiotherapy. Blood transfusion may be required but is not systematic. Acute spleen sequestration occurs in young children and requires immediate hospital referral for transfusion.

The spleen has a combined function of immune defence and quality control of senescent or altered red cells. It is the first organ injured in sickle cell anaemia (SCA) with evidence of hyposplenism present before 12 months in the majority of children. Repeated splenic vaso-occlusion leads to fibrosis and progressive atrophy of the organ (autosplenectomy), which is generally complete by 5 years in SCA. The precise sequence of pathogenic events leading to hyposplenism is unknown. Splenic injury is generally silent and progressive. It can be clinically overt with acute splenic sequestration of red cells, an unpredictable and life-threatening complication in infants. Splenomegaly, with or without hypersplenism, can also occur and can coexist with loss of function. Hyposplenism increases the susceptibility of SCA children to infection with encapsulated bacteria, which is notably reduced by penicillin prophylaxis and immunization. Whether hyposplenism indirectly increases the risk of vaso-occlusion or other circulatory complications remains to be determined., (© 2014 John Wiley & Sons Ltd.)

Hypoxia is a common feature in children with sickle cell disease (SCD) that is inconsistently associated with painful crises and acute chest syndrome. To assess the prevalence and risk factors of hypoxia, we recorded daytime, nocturnal, and postexercise pulse oximetry (SpO2) values in 39 SCD patients with a median age of 10.8 years. Median daytime SpO2 was 97% (range, 89%-100%), and 36% of patients had daytime hypoxia defined as SpO2<96%. Median nocturnal SpO2 was 94.7% (range, 87.7%-99.5%), 50% of patients had nocturnal hypoxia defined as SpO2≤93%, and 11(37%) patients spent more than 10% of their total sleep time with SpO2<90%. Median postexercise SpO2 was 94% (range, 72%-100%) and 44.7% of patients had postexercise hypoxia defined as an SpO2 decrease ≥3% after a 6-minute walk test. Among patients with normal daytime SpO2, 35% had nocturnal and 42% postexercise hypoxia. Compared to 9 patients without daytime, nocturnal, or postexercise hypoxia, 25 patients with hypoxia under at least one of these three conditions had greater anemia severity (P = 0.01), lower HbF levels (P = 0.04), and higher aspartate aminotransferase levels (P = 0.03). Males predominated among patients with postexercise hypoxia (P = 0.004). Hypoxia correlated neither with painful crises nor with acute chest syndrome. Of 32 evaluable patients, 6 (18.8%) had a tricuspid regurgitation velocity ≥2.6 m/s, and this feature was associated with anemia (P = 0.044). Median percentage of the predicted distance covered during a 6-minute walk test was 86% [46-120]; the distance was negatively associated with LDH (P = 0.044) and with a past history of acute chest syndrome (P = 0.009). In conclusion, severe episodes of nocturnal and postexercise hypoxia are common in children with SCD, even those with normal daytime SpO2.

In this issue of Blood, Garcia-Santos et al advance the field of heme regulation, a highly complex process involving iron and globin metabolism. They focus on a key enzyme involved in heme catabolism, heme oxygenase 1 (HO-1), which, ironically, has been poorly investigated in erythroid cells, the largest pool of heme-containing cells.

A 13-year-old girl with homozygous sickle cell disease was referred for vision loss in her left eye of 1 year's duration. Clinical findings were consistent with a past retinal arterial occlusion. In the asymptomatic right eye, spectral domain optical coherence tomography showed a severe atrophy of the inner retinal layers of the temporal median raphe; a significant internal carotid stenosis was also present. We hypothesize that specific atrophy of the retinal temporal median raphe resulted from chronic ischemia. The inner layers of the retina are vascularized by terminal vessels and the median raphe can therefore be regarded as a junction territory; its atrophy may represent an ocular equivalent of a silent border zone cerebral infarct., (Copyright © 2012 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved.)

Splenic sequestration of RBCs with reduced surface area and cellular deformability has long been recognized as contributing to pathogenesis of several RBC disorders, including hereditary spherocytosis. However, the quantitative relationship between the extent of surface area loss and splenic entrapment remains to be defined. To address this issue, in the present study, we perfused ex vivo normal human spleens with RBCs displaying various degrees of surface area loss and monitored the kinetics of their splenic retention. Treatment with increasing concentrations of lysophosphatidylcholine resulted in a dose-dependent reduction of RBC surface area at constant volume, increased osmotic fragility, and decreased deformability. The degree of splenic retention of treated RBCs increased with increasing surface area loss. RBCs with a > 18% average surface area loss (> 27% reduced surface area-to-volume ratio) were rapidly and completely entrapped in the spleen. Surface-deficient RBCs appeared to undergo volume loss after repeated passages through the spleen and escape from splenic retention. The results of the present study for the first time define the critical extent of surface area loss leading to splenic entrapment and identify an adaptive volume regulation mechanism that allows spherocytic RBCs to prolong their life span in circulation. These results have significant implications for understanding the clinical heterogeneity of RBC membrane disorders.

Acute splenic sequestration crisis (ASSC) is an unpredictable life-threatening complication of sickle cell disease (SCD) in infants. Here, our objective was to update available clinical information on ASSC. We retrospectively studied the 190 patients who were diagnosed at birth with SS or Sbeta(0) in the Paris conurbation between 2000 and 2009 and who experienced ASSC. They had 437 ASSC episodes (0.06/patient-year). Median age at the first episode was 1.4 years (0.1-7) and 67% of patients had more than one episode. Age was the only factor predicting recurrence: the risk was lower when the first episode occurred after 2 years versus before 1 year of age (hazard ratio, 0.60; 95% confidence interval, 0.41-0.88; P=0.025). A concomitant clinical event was found in 57% of episodes. The mortality rate was 0.53%. The treatment consisted in watchful waiting without prophylactic blood transfusions or splenectomy in 103 (54%) patients and in a blood transfusion programme in 55 (29%) patients. Overall, splenectomy was performed in 71 (37%) patients, at a median age of 4.5 years (range, 1.9-9.4). In conclusion, aggressive treatment may be warranted in patients experiencing ASSC before 2 years of age. Randomized controlled trials are needed to define the best treatment modalities., (© 2012 Blackwell Publishing Ltd.)

Retention of poorly deformable red blood cells (RBCs) by the human spleen has been recognized as a critical determinant of pathogenesis in hereditary spherocytosis, malaria, and other RBC disorders. Using an ex vivo perfusion system, we had previously shown that retention of Plasmodium falciparum-infected RBCs (Pf-RBCs) occur in the splenic red pulp, upstream from the sinus wall. To experimentally replicate the mechanical sensing of RBCs by the splenic microcirculation, we designed a sorting device where a mixture of 5- to 25-μm-diameter microbeads mimics the geometry of narrow and short interendothelial splenic slits. Heated RBCs, Pf-RBCs, and RBCs from patients with hereditary spherocytosis were retained in the microbead layer, without hemolysis. The retention rates of Pf-RBCs were similar in microbeads and in isolated perfused human spleens. These in vitro results directly confirm the importance of the mechanical sensing of RBCs by the human spleen. In addition, rigid and deformable RBC subpopulations could be separated and characterized at the molecular level, and the device was used to deplete a stored RBC population from its subpopulation of rigid RBCs. This experimental approach may contribute to a better understanding of the role of the spleen in the pathogenesis of inherited and acquired RBC disorders.

Clinical manifestations of Plasmodium falciparum infection are induced by the asexual stages of the parasite that develop inside red blood cells (RBCs). Because splenic microcirculatory beds filter out altered RBCs, the spleen can innately clear subpopulations of infected or uninfected RBC modified during falciparum malaria. The spleen appears more protective against severe manifestations of malaria in naïve than in immune subjects. The spleen-specific pitting function accounts for a large fraction of parasite clearance in artemisinin-treated patients. RBC loss contributes to malarial anemia, a clinical form associated with subacute progression, frequent splenomegaly, and relatively low parasitemia. Stringent splenic clearance of ring-infected RBCs and uninfected, but parasite-altered, RBCs, may altogether exacerbate anemia and reduce the risks of severe complications associated with high parasite loads, such as cerebral malaria. The age of the patient directly influences the risk of severe manifestations. We hypothesize that coevolution resulting in increased splenic clearance of P. falciparum-altered RBCs in children favors the survival of the host and, ultimately, sustained parasite transmission. This analysis of the RBC-spleen dynamic interactions during P falciparum infection reflects both data and hypotheses, and provides a framework on which a more complete immunologic understanding of malaria pathogenesis may be elaborated.

Objectives: In children with sickle cell disease (SCD), chronic transfusion to maintain haemoglobin S (HbS) below 30% markedly decreases both the risk of a first stroke when transcranial Doppler (TCD) ultrasonography shows abnormal cerebral blood flow velocities and the risk of recurrent stroke. Maintaining HbS below 30% may be difficult, especially in countries where blood donors and recipients belong to different ethnic groups and where the availability of closely matched blood products is limited. We assessed the feasibility and efficacy of chronic transfusion with an HbS target of 30% in children with SCD living in the Paris area., Methods: We retrospectively studied 29 children aged 6.8 +/- 3.0 yr (3-15 yr) at inclusion who received chronic transfusion either because of abnormal TCD findings (primary prevention group, PPG, n = 17) or because of a previous cerebrovascular event (secondary prevention group, SPG, n = 12 including nine with a history of stroke and three of transient ischaemic attacks)., Results: Mean follow-up was 3.5 +/- 3.0 yr (0.5-12 yr). No cases of stroke occurred in the PPG. In the SPG, one patient with a history of stroke and severe cerebrovascular disease had a recurrence after 11 yr of chronic transfusion, when the HbS level was 20%. The stroke recurrence rate (SPG group) was 1.6/100 patient-years. Mean HbS levels before and after transfusion were 30 +/- 10% and 20.6 +/- 7%, respectively. Two patients acquired red-cell alloantibodies. Of the 29 patients, 22 required iron chelation., Conclusions: Regular transfusion maintaining HbS below 30% is feasible and safe in children with SCD in France and protects from overt stroke.

We report on a 12-year-old patient from Congo who presented acute chorea following cardiac surgery for poststreptococcal mitral valvulopathy. She showed severe and asymmetrical chorea, associated with motor impersistence and agitation. Biological investigations disclosed inflammatory signs and brain MRI was normal. Due to the negative results of the biological and morphological investigations, the diagnosis of Sydenham chorea was suspected. High doses of oral steroids resulted in a dramatic improvement of the chorea as well as the behavior disturbance within 1 month. Sydenham chorea is not an unusual complication of rheumatic fever. Usually, patients develop chorea a few weeks after beta-hemolytic streptococcal pharyngitis. Details on its pathophysiology remain to be determined. Our case highlights its possible onset in the postoperative period if alternative etiologies of infantile chorea have been excluded.

A retrospective study was conducted to assess changes in cerebrovascular lesions, as assessed by magnetic resonance (MR) imaging and angiography in 18 children with sickle cell disease (SCD) receiving optimised chronic transfusions for primary stroke prevention (abnormal transcranial Doppler flow, nine patients, median follow-up 14.3 months (range, 7.9-48.9)) or secondary stroke prevention (nine patients, median follow-up 59.6 months (range, 11.0-127.9)). An experienced neuroradiologist blinded to patient data reviewed the 41 MR scans (median/patient, three (2-4)). Standard scores were used to evaluate parenchymal and vascular abnormalities at baseline and last follow-up. Within-patient score changes evaluated using Wilcoxon's paired rank test indicated lesion progression in the secondary-prevention group (p = 0.027). Optimised transfusion therapy does not prevent progression of cerebral vasculopathy in SCD children with a history of stroke.

The current paradigm in Plasmodium falciparum malaria pathogenesis states that young, ring-infected erythrocytes (rings) circulate in peripheral blood and that mature stages are sequestered in the vasculature, avoiding clearance by the spleen. Through ex vivo perfusion of human spleens, we examined the interaction of this unique blood-filtering organ with P falciparum-infected erythrocytes. As predicted, mature stages were retained. However, more than 50% of rings were also retained and accumulated upstream from endothelial sinus wall slits of the open, slow red pulp microcirculation. Ten percent of rings were retained at each spleen passage, a rate matching the proportion of blood flowing through the slow circulatory compartment established in parallel using spleen contrast-enhanced ultrasonography in healthy volunteers. Rings displayed a mildly but significantly reduced elongation index, consistent with a retention process, due to their altered mechanical properties. This raises the new paradigm of a heterogeneous ring population, the less deformable subset being retained in the spleen, thereby reducing the parasite biomass that will sequester in vital organs, influencing the risk of severe complications, such as cerebral malaria or severe anemia. Cryptic ring retention uncovers a new role for the spleen in the control of parasite density, opening novel intervention opportunities.

The spleen plays a central role in the pathophysiology of several potentially severe diseases such as inherited red cell membrane disorders, hemolytic anemias, and malaria. Research on these diseases is hampered by ethical constraints that limit human spleen tissue explorations. We identified a surgical situation--left splenopancreatectomy for benign pancreas tumors--allowing spleen retrieval at no risk for patients. Ex vivo perfusion of retrieved intact spleens for 4 to 6 hours maintained a preserved parenchymal structure, vascular flow, and metabolic activity. Function preservation was assessed by testing the ability of isolated-perfused spleens to retain Plasmodium falciparum-infected erythrocytes preexposed to the antimalarial drug artesunate (Art-iRBCs). More than 95% of Art-iRBCs were cleared from the perfusate in 2 hours. At each transit through isolated-perfused spleens, parasite remnants were removed from 0.2% to 0.23% of Art-iRBCs, a proportion consistent with the 0.02% to 1% pitting rate previously established in artesunate-treated patients. Histologic analysis showed that more than 90% of Art-iRBCs were retained and processed in the red pulp, providing the first direct evidence of a zone-dependent parasite clearance by the human spleen. Human-specific physiologic or pathophysiologic mechanisms involving clearing or processing functions of the spleen can now be experimentally explored in a human tissue context.

Two hundred twenty-five SCD children have been enrolled in a study assessing the tolerability of hydroxyurea treatment. Mean age at inclusion was 9.2+/-4.4 years, median duration of treatment was 3.8 years. Ten and 75 patients have been treated respectively for more than 10 and 5 years. No severe side effect was related to hydroxyurea treatment, which was discontinued in 81 children mainly for treatment failure (30 cases) or non-compliance (17 cases). Treatment was also withdrawn in 5 of 6 children who had developed hypersplenism, in 3 because of a pathological transcranial Doppler, and in 2 after a stroke.

Infantile rumination can be defined as self-induced regurgitation of previously swallowed food. Because it can lead to potential somatic complications and because it implies dysfunctional mother-child bonding, both a pediatric and psychiatric approach is needed. The treatment must be somatic (nutritional) and psychological (intensive nursing, mother-baby psychotherapy). Two case studies illustrate this rare but impressive picture.

Unlabelled: The relevance of World Health Organization (WHO) criteria for severe malaria has not been assessed in non-immune children. The objectives of this study were (i) to evaluate the significance of 1990 WHO definition reconsidered in 2000 on distribution and lethality of severe cases in children admitted with falciparum malaria, and (ii) to contribute to the study of relevance of the WHO severe criteria in Dakar, an hypoendemic area in Senegal., Patients and Methods: The 1990 WHO criteria, respiratory distress and platelet counts were prospectively collected in 1997-99 from children admitted to Hôpital Principal de Dakar, Senegal, with falciparum malaria diagnosed on a thick blood film. This method allowed also the definition of severe cases according to 2000 WHO criteria., Results: Among 311 patients (median age: 8 years old), according to the 2000 WHO criteria, the frequency of severe malaria cases was increased by 23% (75% versus 52%) and case-fatality rates thereof were decreased by 5% (17% versus 12%) compared with 1990 WHO definition. One death occurred among cases defined as severe on admission only according to criteria modified by WHO in 2000. A multivariate logistic regression model identified several independent prognostic factors: cerebral malaria, hypoglycaemia, respiratory distress, renal failure, collapse, abnormal bleedings, pupillary abnormalities and thrombocytopaenia defined as a platelet count below 100,000/mm3. A significant association (p < 0.001) was observed between platelet count increase and consciousness level improvement, evaluated on day of first platelet count control (time from admission: 1-7 d). Among survivors, a lesser improvement in coma score was associated with a decrease in platelet counts (p < 0.04)., Conclusions: The 1990 WHO criteria, which predicted death among malaria cases in children living under stable falciparum transmission, are relevant in this series of non-immune children living in a low and seasonal transmission. Nevertheless new WHO criteria showed poor prognostic significance. However, the 2000 WHO definition was highly sensitive to detect severe malaria cases. These findings should be considered for managing severe malaria in migrant children.

The incidence of childhood heart disease in developing countries is high, but access to cardiac surgery is limited. This mismatch has given rise to numerous humanitarian programs aimed at sending children abroad for surgical treatment. However little is available about the long-term outcome of these interventions. In 1999 we conducted a retrospective study of 168 Senegalese children undergoing follow-up at the Principal Hospital in Dakar after being transferred to Europe or the Ivory Coast for surgical treatment thanks to the Terre des Hommes Association. A total of 85 children presented congenital heart disease (CHD) and 83 presented acquired heart disease (AHD). Fifteen patients did not undergo surgery due to either contraindications or preoperative death. At the end of study, 23 children had been lost to follow-up mostly from the CHA group and presumably some were cured. Outcome was verifiable in the remaining 145 patients with a median follow-up of 5.6 years. Ninety-seven patients were cured or undergoing surveillance. Quality of life was better in the CHD group (p = 0.047). Forty-eight patients died including 16 in the CHD group and 32 in the AHD group. Perioperative mortality (n = 19) was lower and late mortality (n = 29) was higher in the AHD group (p = 0.005). In the AHD group compliance with surveillance was better for children with valve prostheses. In children treated for isolated mitral valve insufficiency, late mortality was higher after valve replacement than valve repair (p = 0.04). In absence of comparative study data, high mortality was due in part to the long delay between the decision to send the patient abroad and the actual evacuation. These findings support humanitarian action to promote cardiac surgery in developing countries.

Thrombocytopenia is a common finding in malaria, but its prognostic value has not been addressed in children. The relationship between thrombocytopenia (platelet count < 100,000/mm3 on admission) and severity and outcome was investigated prospectively in children hospitalized with falciparum malaria in Dakar, Senegal, an area that is hypoendemic for malaria. Of 288 falciparum cases, 215 matched the 2000 World Health Organization definition of severe malaria. Median platelet counts were lower (98,000/mm3 versus 139,000/mm3; P < 0.02) among severe cases than in mild cases, and in children who died than among those who recovered (68,500/mm3 versus 109,000/mm3; P < 0.002). In severe cases, children presenting with a platelet count < 100,000/mm3 were more likely to die (odds ratio [OR] = 6.31, 95% confidence interval [CI] = 2.0-26.0). Moreover, multivariate analysis identified thrombocytopenia as an independent predictor of death (OR = 13.3, 95% CI = 3.2-55.1). Our data show an association between thrombocytopenia and either severity or prognosis in childhood falciparum malaria.

Nebulization is a useful administration route in cystic fibrosis (CF) as it delivers antibiotics directly to the endobronchial site of infection and is associated with decreased toxicity because of limited systemic absorption. It is assumed that the concentration of antibiotics in bronchial secretions should be as high as 10 times the minimum inhibiting concentration to allow penetration of antibiotics into biofilms, suppress inhibitory factors and promote bactericidal effectiveness. However, effective aerosol delivery is compromised by nebulizers with limited capacity to produce particles of a size in the respirable range. Three antibiotics are commonly used for inhalation: tobramycin, amikacin and colistin (colomycin). Placebo-controlled studies evaluating antibiotic aerosol maintenance in stable patients chronically infected with Pseudomonas aeruginosa indicate a significant improvement of lung function and a reduction of the number of hospital admissions for an acute exacerbation of CF. TOBI is a recently marketed preservative- and sulfate-free formula of tobramycin, specially designed for diffusion in the bronchioles and optimal tolerance. A wide-scope study involving 520 patients compared TOBI (300 mg twice daily; n = 258) with placebo (n = 262) for three 28-day cycles with each cycle separated by a 28-day period of no treatment. Respiratory function was significantly improved as early as in the second week and remained so for the rest of the trial even during periods without aerosol treatment. There was also a parallel decrease in the relative risk of hospitalization, the number of days of hospitalization and the number of days on intravenous antipyocyanic treatment. Toxicity studies carried out so far have shown no renal or ototoxicity with nebulized tobramycin. Introduction or selection of resistant bacteria is relatively rare but remains a matter of concern. Aerosol maintenance treatment with an appropriate antibiotic in a high enough dosage can be recommended for patients with CF who are chronically infected with P. aeruginosa.

Prion diseases are rare neurologic affections with a poor prognosis, occurring in both humans and animals. Creutzfeldt-Jakob disease (CJD) secondary to human extracted growth hormone treatment is the most frequent condition in pediatrics. In 1994, a new type of CJD (variant CJD) was described in young adults in the United Kingdom, only 10 years after the bovine spongiform encephalopathy epidemic, with recent works showing a direct relationship between the bovine epidemic and the human cases. An accumulation of a single protein called the prion protein (PrP) has been discovered in the brain in all of these cases, animal and human, leading to the hypothesis that a new infectious agent could proceed without any nuclear acid information; another hypothesis is that of a still unknown viral agent. The PRNP gene encoding for this PrP protein is well described: some mutations and a polymorphism in the 129th codon have been shown to be implicated in many cases of CJD. PrP is a ubiquitous protein, with yet unknown physiological function. There are still many questions to be answered: shall we expect new pediatric cases of variant CJD? Assuming that animal-human contamination is related to alimentation, are there other ways of contamination.