[Erythrapheresis in children with sickle cell disease, experience of a paediatric apheresis unit]. / Érythraphérèses chez l'enfant drépanocytaire, expérience d'une unité d'aphérèse pédiatrique.

Erythrocyte exchanges on cell separators can be used in children with sickle cell disease and are effective in lowering the level of haemoglobin S. Of the 938 aphereses performed in 2020 in our unit, we observed a low rate of failure of procedures and few complications. Ninety-six percent of erythraphereses were performed in the context of chronic exchange programs, in more than 80% of cases for cerebral vasculopathy or after the occurrence of ischemic strokes. Less than 4% of the procedures were performed for specific indications (preparation for cholecystectomy most often). The vascular access is rarely an obstacle to the realisation of the apheresis. In case of insufficient venous capital, installing an arteriovenous fistula may be considered. Depending on the child's weight, haemoglobin level, and the severity of the sickle cell anaemia, precautions may be necessary when priming the procedure. Nurses experienced in paediatric apheresis and a good medical knowledge of sickle cell disease allowed us to use this technique from the age of 3years and the weight of 15kg.

[Perception and assessment of pain by caregiver and adolescent with sickle cell disease: The impact of the patient's anxiety]. / Perception et évaluation de la douleur par le soignant et l'adolescent drépanocytaire : impact de l'anxiété du patient.

Pain is the main symptom in sickle cell disease and is a major issue in its management. Its complexity often makes assessment difficult for both patients and caregivers. This study looks for a link between anxiety in children with sickle cell disease at the beginning of their hospital stay and the difficulties experienced by caregivers to assess their pain. Forty teenagers hospitalized for a vaso-occlusive crisis were included in this prospective study. To determine which patients were "difficult to assess," a self-assessment of pain combined with a nursing assessment were proposed to patients (NS [numerical scale] and FLACC [Face Legs Activity Cry Consolability]). Feedback from specialized physicians was collected. In this study, no objective criteria allowed us to determine whether patients were "difficult to assess." At the beginning of the hospital stay, self-assessment for pain and nurse assessment with the NS matched. In this context, the FLACC scale did not assist in determining the pain score accurately. Patients identified as difficult to assess by physicians are more anxious than others.

[Development of psychological and intellectual performance in transplanted sickle cell disease patients: a prospective study from pretransplant period to 5 years after HSCT]. / Développement psycho-intellectuel des enfants drépanocytaires ayant reçu une allogreffe de cellules souches hématopoïétiques.

RATIONALE: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for sickle cell disease (SCD). Cerebral vasculopathy was the principal indication for transplantation. These children could present impaired neuropsychological development related to different causes, hence the value of exploring their intellectual capacities before and after transplantation. MATERIAL AND METHODS: Prospective longitudinal study from 1992 to 2006 in all transplanted SCD patients. The patients were assessed using Wechsler scales with four different indices: verbal comprehension, perceptual reasoning, working memory, and processing speed (PSI), providing a full-scale intellectual quotient (IQ). RESULTS: Fifteen SCD patients (8 females and 7 males; mean age, 8.9 years) were evaluated before and 36 and 60 months after transplantation. All were from Africa and lived in France. All patients except 2 had experienced ischemic stroke before HSCT. The median full-scale IQ was 87, 94, and 94 before transplantation and 36 months and 60 months after HSCT, respectively. DISCUSSION: At pre-HSCT evaluation, full-scale IQ was considered as "low average". This relatively poor result could be related to impairment of PSI, which reflects frequent graphic and motor abnormalities related to the previous stroke experienced by almost all patients. At 3 years after HSCT, all indices including IQ had increased. Only the PSI had decreased, this observation being potentially related to previous stroke and to the depression frequently experienced by the transplant recipient patient after the acute phase, when the disease is cured. At 5 years after HSCT, the median full-scale IQ was stable and the PSI had increased. CONCLUSION: At the end of follow-up, the patients improved their physical and psychological well-being. This allowed them to build projects for the future and to manifest the desire of becoming an adult. Bone marrow transplantation in this cohort of children with SCD and severe cerebral vasculopathy is associated with improved performance as measured by the Wechsler scale.

Laparoscopic approach as primary treatment of common bile duct stones in children.

BACKGROUND: Preoperative endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy (ES) are an effective strategy for choledocholithiasis, but complications such as pancreatitis and outcome in children are unknown. The laparoscopic cholecystectomy became the new gold standard in children for cholelithiasis. For the choledocholithiasis in children, the attitude is more controversial. We analyzed our series of laparoscopic approach for the management of choledocholithiasis in children to determine if it is an effective procedure. PATIENTS AND METHOD: Between 1996 and 2001, 126 children were treated for cholelithiasis in our institution; 13 children (10.3%) were managed for a choledocholithiasis. We reviewed age at symptom onset results of paraclinical examinations, the type of laparoscopic management, and postoperative outcome. RESULTS: The mean age at clinical signs was 9.9 years (range, 3 months-15.5 years). One child was excluded because he had a preoperative ES. Twelve children had a laparoscopic cholecystectomy and cholangiogram at the same time. A choledocholithiasis was found in 10 cases. A flush of the common bile duct (CBD) was performed in all cases with a 3F or 5F ureteral catheter; the stone was pushed into the duodenum in 3 cases and successfully extracted in 3 with a 4F Dormia or Fogarty catheter. One child needed a conversion to open surgery. Three times, an ES was necessary in postoperative course in each case for clinical and biologic signs of CBD obstruction or pancreatitis (30%). All children are symptom-free with an average follow-up of 28 months. CONCLUSION: Laparoscopic CBD exploration for choledocholithiasis can be performed safely in children at the time of cholecystectomy and can clear all of the stones in the CBD in two thirds of cases. If there is residual obstruction, a postoperative ES can be performed. We suggest primary treatment of choledocholithiasis by laparoscopic approach in children.

Pediatric laparoscopic splenectomy: benefits of the anterior approach.

INTRODUCTION: Splenectomy is frequently performed in children for various hematologic and autoimmune disorders. We reviewed our indication for splenectomy, our technique of laparoscopic, splenectomy, and our results. The aim of this study was to show if an anterior approach with elective vessel endoligature in a patient in decubitus position was a better and safer approach than the other techniques previously published. PATIENTS AND METHODS: Between January 1996 and December 2002, 54 children underwent laparoscopic splenectomy. We use the anterior pedicle approach and elective vessel endoligature in order to prevent persistence of any exogenous material. Sixteen children also had a concomitant cholecystectomy. Their age ranged between 1 and 18 years (mean 7.5 years). Twenty children had hereditary spherocytosis, 15 were affected by sickle cell disease, six had an idiopathic thrombocytopenia, four had beta-thalassemia, and nine another hemolytic disease. RESULTS: Mean operative time was 150 min (range, 115-230 min). Hospital stays ranged from 3 to 15 days (mean: 5.4). Seven patients had complications (four pneumonia and three deep abscess with successful antibiotic treatment). Median follow-up was 42 months (2 months-6 years) without problems regarding procedure. DISCUSSION: With this technique consisting in first elective arterial and secondary venal ligature, we preserved blood splenic sequestration and pancreatic tail lesion. The procedure is safer. For us, considering the low complication rate for this type of patient, and the advantages of a small abdominal trauma in the postoperative period, laparoscopy with anterior approach for elective splenectomy and eventual cholecystectomy in hematologic disorders is the best technique.

[Laparoscopic splenectomy in children: experience and results]. / Splénectomies coelioscopiques chez l'enfant: expérience et résultats.

UNLABELLED: Pediatric laparoscopic splenectomy is a relatively new surgical procedure. Advances in instrumentation and technique now make this procedure possible. Splenectomy is frequently performed in children for various hematologic and autoimmune diseases. PATIENTS AND METHODS: This article reviews the indication for splenectomy, the technique of laparoscopic splenectomy and our results. Between January 1996 and January 2000, 23 children underwent laparoscopic splenectomy. Three of them also had a concomitant cholecystectomy. Their ages ranged from three to 14 years. Nine children had hereditary spherocytosis, four were affected by sickle cell disease, three had an idiopathic thrombocytopenia and three a hemolytic disease. One patient was converted. RESULTS: Mean operative time was 170 min (range, 115-230 min). Hospital stay ranged from three to 15 days (median, 6). Five patients had complications (three pneumonia and two deep abscesses). Median follow-up was 20 months (two months to four years) without problems regarding procedure. CONCLUSION: Regarding the low complication rate for this type of patient and the advantages of a small abdominal trauma in the postoperative period, the laparoscopic approach for elective splenectomy in hematological disorders is the technique of choice.

[Neonatal screening for sickle cell anemia: evaluation of a five-year experience in an area of northern Paris]. / Dépistage néonatal ciblé de la drépanocytose: bilan de cinq années d'expérience dans le nord-francilien.

UNLABELLED: We report a five-year experience of targeted neonatal screening for sickle cell disease in the northern part of the Paris area as well as the follow-up procedure of screened patients. POPULATION: This geographic area in France is characterized by a high frequency of populations at risk for sickle cell disease. RESULTS: Among 115,480 tested newborns, 250 patients were diagnosed (frequency: 1/462). The quality of the screening was attested by the high frequency (5.34%) of newborn carriers for a hemoglobin abnormality (n = 6168). We developed an optimized strategy which avoids the majority of pitfalls (false positive and false negative responses), except for S/HPFH. More than 95% of sickle cell disease was followed, the majority by medical sickle cell disease experts from hospitals. Only two deaths were recorded during this time period. CONCLUSION: We demonstrate the efficiency of targeting the proposed methodological strategy and the follow-up of affected newborns, a major argument demonstrating the importance of newborn screening.

Elective laparoscopic cholecystectomy.

BACKGROUND: Gallbladder stones are very common in patients with sickle cell disease and are the cause of recurrent abdominal pain. Their management has been highly controversial, especially for children. Nonoperated patients and those treated on an emergency basis have a very high rate of morbidity (>50%). METHODS: We performed a retrospective review of a series of 29 homozygous SS sickle cell children who underwent laparoscopic cholecystectomy between 1991 and April 1998. RESULTS: Only in one case a conversion was necessary (early in the series). Exploration of the common bile duct was done via intraoperative cholangiography. There were no mortalities. The morbidity rate was 17%; (however, of the five patients concerned, four suffered from hyperthermia for 2 days. All of the children were improved and enjoyed resolution of their abdominal pain. CONCLUSIONS: We believe that elective laparoscopic cholecystectomy at the earliest time possible, along with correct perioperative management, is the treatment of choice for cholelithiasis in children with sickle cell disease.

Strategy linking several analytical methods of neonatal screening for sickle cell disease.

BACKGROUND: The French national programme for the neonatal screening of sickle cell disease (SCD) was set up in 1995. This screening is targeted at newborn infants at risk. Over 5 years, 115,480 newborn infants were tested from 80 maternity departments from the northern part of the Paris area. 250 Patients with SCD were identified--that is, one in 462 newborn infants tested. Carriers for a haemoglobin (Hb) variant are frequent (5.34%). Some uncommon Hb variants were also identified, which gave rise to pitfalls to the testing when associated with HbS: HbKorle-Bu, HbHope, HbBougardirey-Mali, and HbLadésirade (4% of SS-like profiles). OBJECTIVE: An effective screening strategy was developed to avoid these false positive and false negative responses. METHODS: Isoelectric focusing (IEF), the method of primary screening, is rapid and inexpensive. Cation exchange high performance liquid chromatography (CE-HPLC), which is automated, fast, and quantitative was selected as a secondary method. RESULTS: IEF diagnosed normal profiles in 89% of the tested samples from newborn infants. CE-HPLC identified most of the common Hb variants by their retention time and the measure of HbA/HbS ratio, important for the differential diagnosis between an asymptomatic HbS carrier and an HbS/beta+thal compound heterozygote. Furthermore, the high sensitivity of the CE-HPLC detected as little as 0.5% of a Hb variant. This avoided false negatives in samples from premature or transfused newborn infants. All samples with SS-like profiles were confirmed with a second CE-HPLC with another programme. A combination of these three methods confirmed the status of 99.7% of the samples from the tested newborn infants. Some cases required a reverse phase-HPLC method (for gamma-globin or alpha-globin chain variants). Finally, some exceptional samples required confirmation by testing DNA extracted with Güthrie paper for a precise diagnosis. CONCLUSIONS: This effective strategy combining several methods dramatically reduces the risk of errors. Many families are thus spared unnecessary worrying recalls. The only unavoidable cause of false positives remains the HbS/hereditary fetal Hb (HPFH).

Acute clinical events in 299 homozygous sickle cell patients living in France. French Study Group on Sickle Cell Disease.

A subset of 299 patients with homozygous sickle cell anaemia, enrolled in the cohort of the French Study Group on sickle cell disease (SCD), was investigated in this study. The majority of patients were children (mean age 10.1 +/- 5.8 yr) of first generation immigrants from Western and Central Africa, the others originated from the French West Indies (20.2%). We report the frequency of the main clinical events (mean follow-up 4.2 +/- 2.2 yr). The prevalence of meningitis-septicaemia and osteomyelitis was, respectively, 11.4% and 12% acute chest syndrome was observed in 134 patients (44.8%). Twenty patients (6.7%) developed stroke with peak prevalence at 10-15 yr of age. One hundred and seventy-two patients (58%) suffered from one or more painful sickle cell crises, while the others (42.5%) never suffered from pain. The overall frequency of acute anaemic episodes was 50.5%, (acute aplastic anaemia 46%; acute splenic sequestration 26%). A group of 27 patients were asymptomatic (follow-up > 3 yr). Epistatic mechanisms influencing SCD were studied. Coinherited alpha-thalassemia strongly reduced the risk of stroke (p <0.001) and increased that of painful crises (p < 0.02). There was a low prevalence of Senegal and Bantu (CAR) betas-chromosomes in patients with meningitis (p <0.04) and osteomyelitis (p < 0.03). Prevalence of Senegal betas-chromosomes was lower in the asymptomatic group of 27 patients (p < 0.02). The patients come from a population of unmixed immigrants in whom the beta-globin gene haplotype strongly reflects the geographic origin and identifies subgroups with a homogenous genetic background. Thus the observed effects might result more from differences in as yet unidentified determinants in the genetic background than from the direct linkage with differences in the beta-globin gene locus.

Multicenter prospective study of children with sickle cell disease: radiographic and psychometric correlation.

After obtaining familial informed consent, between January 1996 and July 1997, 173 children (5 to 15 years old) with sickle cell disease were enrolled in a prospective multicenter study using blood screening, transcranial Doppler ultrasonography (n = 143), cerebral magnetic resonance imaging (n = 144), and neuropsychologic performance evaluation (n = 156) (Wechsler Intelligence tests WISC-III, WIPPSI-R), which were also performed in 76 sibling controls (5 to 15 years old). Among the 173 patients with sickle cell disease (155 homozygous for hemoglobin SS, 8 sickle cell beta0 thalassemia, 3 sickle cell beta+ thalassemia, 7 sickle cell hemoglobin C disease SC), 12 (6.9%) had a history of overt stroke, and the incidence of abnormal transcranial Doppler ultrasonography (defined as mean middle cerebral artery velocity > 200 cm/sec or absent) was 8.4% in the overall study population and 9.6% in patients with homozygous sickle cell anemia The silent stroke rate was 15%. Significantly impaired cognitive functioning was observed in sickle cell disease patients with a history of stroke (Performance IQ and Full Scale IQ), but also in patients with silent strokes (Similarities, Vocabulary, and Verbal Comprehension). However, infarcts on magnetic resonance imaging were not the only factors of cognitive deficit: Verbal IQ, Performance IQ, and Full Scale IQ were strongly impaired in patients with severe chronic anemia (hematocrit < or = 20%) and in those with thrombocytosis (platelets > 500 x 10(9)/L). Multivariate logistic regression analysis showed that abnormal magnetic resonance imaging (odds ratio [OR] = 2.76) (P = .047), hematocrit < or =20% (OR = 5.85) (P = .005), and platelets > 500 x 10(9)/L (OR = 3.99) (P = .004) were independent factors of cognitive deficiency (Full Scale IQ < 75) in sickle cell disease patients. The unfavorable effect of low hematocrit has already been suggested, but this is the first report concerning an effect of thrombocytosis and showing that silent stroke alone is not a factor of cognitive deficit when not associated with low hematocrit or thrombocytosis. The effect of hydroxyurea, which is known to increase hematocrit and decrease platelet count, on cognitive functioning of sickle cell patients should be evaluated prospectively.

[Development of care activities for children with sickle cell disease at the Robert-Debré Hospital (Paris), between 1992 and 1996]. / Evolution de l'activité liée à la drépanocytose à l'hôpital Robert-Debré (Paris), entre 1992 et 1996.

AIM: In recent years, physicians at the Robert-Debré pediatric hospital in Paris perceived an increase in activity linked to sickle cell disease care. Our study had two objectives: first, to describe the evolution of care for children with sickle cell disease in the hospital, then, if a heavier intensity of care was shown, to try to investigate its causes. METHODS AND PATIENTS: We conducted a retrospective study using two strategies. On one hand, we compared the group of children followed up in 1992 with the group of children followed up in 1996 for their phenotype and hospitalizations (frequency, length of stay and type of complications), on the other hand, we described the course of complications and hospitalizations in the cohort of children followed from 1992 to 1996. Children were spotted through lists established by the 'Center for sickle cell disease', which coordinates the follow-up of all sickle cell patients in the hospital. Data came from the hospital's information system, and from all (medical, nursing, and social) individual records. RESULTS: The major result of this study shows an increasing activity linked to sickle cell disease care in this hospital: multiplication of hospitalizations and increasing work load for the healthcare teams. This situation is due to a larger recruitment, a higher emergency hospitalization rate, and an increasing rate of complications among the sickle cell children. The children's ageing is part of the explanation. The work load for the healthcare team linked to each hospitalization has also grown, as shown by an increasing rate of morphine prescription.

Protein truncation test of LYST reveals heterogenous mutations in patients with Chediak-Higashi syndrome.

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder in which an immune deficiency occurs in association with pigmentation abnormalities. Most patients who do not undergo bone marrow transplantation die of a lymphoproliferative syndrome, though some patients with CHS have a relatively milder clinical course of the disease. The large size of the LYST gene, defective in CHS, has made it difficult to screen for mutations in a large number of patients. Only 8 mutations have been identified so far, and all lead to a truncated LYST protein. We conducted protein truncation tests on this gene in 8 patients with CHS. Different LYST mutations were identified in all subjects through this approach, strengthening the observation of a high frequency of truncated LYST proteins as the genetic cause of CHS.

Defective CTLA-4 cycling pathway in Chediak-Higashi syndrome: a possible mechanism for deregulation of T lymphocyte activation.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, also known as CD152) has been shown to play a major role in the regulation of T cell activation. Its membrane expression is highly regulated by endocytosis and trafficking through the secretory lysosome pathway. Chediak-Higashi syndrome (CHS) is an inherited disorder caused by mutations in the lysosomal trafficking regulator gene, LYST. It results in defective membrane targeting of the proteins present in secretory lysosomes, and it is associated with a variety of features, including a lymphoproliferative syndrome with hemophagocytosis. The murine equivalent of CHS, beige mice, present similar characteristics but do not develop the lymphoproliferative syndrome. We show herein that CTLA-4 is present in enlarged, abnormal vesicles in CHS T cells and is not properly expressed at the cell surface after T cell activation, whereas its surface expression is not impaired. It is therefore proposed that the defective surface expression of CTLA-4 by CHS T cells is involved in the generation of lymphoproliferative disease. This observation may provide insight into the role of CTLA-4 in humans.

[Transfusion in sickle cell anemia]. / La transfusion dans la drépanocytose.

Although blood transfusion (BT) therapy remains a key component of the weaponry used to treat acute and chronic sickle cell disease complications, its indications and modalities are currently the focus of a critical reappraisal prompted by the introduction of hydroxyurea, recent improvements in allogeneic bone marrow transplantation, and increasing attention to safety concerns. Expected benefits of each BT should be carefully weighed against the risks of infections, immunologic complications, and iron overload. Simple or exchange BT can be used. In emergency situations, the only effective means of improving tissue oxygenation and limiting blood vessel occlusion is dilution or removal of HbS by simple or exchange BT, respectively; simple BT is indicated in severe anemia or acute hypovolemia and exchange BT in acute vasoocclusive crisis or acute infection. In nonemergency situations, long-term exchange BT programs geared to maintain the HbS level around 30% are used to stabilize existing lesions and to prevent recurrences; they have been proved effective in preventing recurrent stroke in patients who are not candidates for allogeneic bone marrow transplantation. Situations in which BT therapy is widely used despite controversy regarding its value and modalities include the prevention of complications of pregnancy, the prevention of perioperative complications, and the prevention of recurrences of severe vaso occlusive crisis in patients eligible for hydroxyurea therapy. Advances have been made in the minimization of BT-related complications (alloimmunization, viral infections, iron overload) through critical appraisal of the need for each BT, careful selection of the most appropriate blood product, and a change in BT technique resulting in a reduction in the number of blood donors.

Anti-B-cell monoclonal antibody treatment of severe posttransplant B-lymphoproliferative disorder: prognostic factors and long-term outcome.

B-lymphoproliferative disorder (BLPD) is a rare but severe complication of organ and bone marrow transplantation (BMT). Profound cytotoxic T-cell deficiency is thought to allow the outgrowth of Epstein-Barr virus-transformed B cells. When possible, reduction of immunosuppressive treatment or surgery for localized disease may cure BLPD. Therapeutic approaches using chemotherapy or antiviral drugs have limited effects on survival. Adoptive immunotherapy with donor T-cell infusions has given promising results in BMT recipients. We previously reported that administration of two monoclonal anti-B-cell antibodies (anti-CD21 and anti-CD24) could contribute to the control of oligoclonal BLPD. Here we report the long-term results of treatment with these monoclonal anti-B-cell antibodies for cases of severe BLPD. In an open multicenter trial, 58 patients in whom aggressive B-cell lymphoproliferative disorder developed after BMT (n = 27) or organ (n = 31) transplantation received 0.2 mg/kg/d of specific anti-CD21 and anti-CD24 murine monoclonal antibodies (MoAbs) for 10 days. The treatment was well tolerated. Thirty-six of the 59 episodes of BLPD in the 58 patients presented complete remission (61%). The relapse rate was low (3 of 36, 8%). Multivariate analysis identified the following risk factors for partial or no response to anti-B-cell MoAb therapy: multivisceral disease (P

Correction of Fas (CD95) deficiency by haploidentical bone marrow transplantation.

Recently, an inherited syndrome characterized by nonmalignant lymphoproliferation with autoimmune manifestations, caused by mutations of the Fas (CD95) receptor gene has been described. Because of disease severity, i.e. unremitting lymphoproliferation in a child with complete Fas deficiency, a haploidentical bone marrow transplantation (BMT) was performed despite the known resistance of Fas-deficient lpr mice to bone marrow transplantation. Marrow graft was rejected early; however, a second attempt using bone marrow from the mother led to engraftment and to control of lymphoproliferation and of autoimmune thrombocytopenia up to the last follow-up at 24 months after BMT. This single case shows that resistance to bone marrow engraftment caused by survival of Fas-deficient cells can be overcome.

Major histocompatibility complex class II deficiency needs an early diagnosis: report of a case.

Major histocompatibility complex (MHC) class II deficiency is a rare primary immunodeficiency disorder characterized by defects in human leukocyte antigen class II expression, inconsistent expression of human leukocyte class I molecules, and a lack of cellular and humoral immune responses to foreign antigens. Clinical onset occurs early in life with recurrent infections and chronic diarrhea. The prognosis is poor, and mean age at the time of death is 4 years. The only curative treatment is bone marrow transplantation (BMT), which allows the immune system's reconstitution. BMT should be done early in life, because long-term survival seems to depend on the number of previous viral infections. We report the case of an MHC class II deficiency discovered late in a 4-year-old girl by means of immunohistochemistry of small bowel biopsy revealing the absence of MHC class II expression. The child received a BMT twice but died because of a overwhelming viral infection. This case underlines the necessity to explore children presenting with infections and chronic diarrhea in order to find MHC class II deficiency. Usually, diagnosis is performed on cytospins, but when it has been missed clinically, it can be performed by using immunohistochemistry on small bowel biopsies.