Red blood cell exchange in children and adolescents with sickle cell disease.

Automatic red blood cell exchange i.e. using devices (RBCX) has become a standard therapy to remove abnormal red blood cells (RBC) in adults and children affected by sickle cell disease (SCD). This treatment is performed both in emergency to treat acute complications and through a regular program of RBCX to prevent the recurrence of complications. However, small children, i.e. those with a low body weight, height and total blood volume, are at risk of relative hypovolemia and metabolic complications during the procedure. Moreover, the peripheral venous access is limited among young children, which requires alternative short- or long-term venous access. These two main limiting factors necessitate adaptations of the procedures and subsequent monitoring during and after the sessions. However, performing RBCX in children requires other adaptations and cautions that must be considered. Our review summarizes the limits, safety precautions and the adaptations of the techniques to ensure RBCX in children.

Age-specific characteristics of neutrophilic dermatoses and neutrophilic diseases in children.

BACKGROUND: Our suggested 'modern' concepts of 'neutrophilic dermatoses' (ND) and 'neutrophilic disease' were based on observations in adult patients and have not been studied in paediatric patients. Only a minority of ND occurs in children, and little is known about age-specific characteristics. OBJECTIVES: To describe age-specific characteristics of ND in children and to study whether our suggested 'modern' classification of ND may be applied to children. METHODS: We conducted a retrospective multicentre study in a French cohort of 27 paediatric patients diagnosed with pyoderma gangrenosum (PG) or Sweet's syndrome (SS). RESULTS: Demographics and distribution of typical/atypical forms were similar in patients diagnosed with PG and SS. Atypical ND were more frequent in infants (90%), when compared to young children (60%) and adolescents (33%). Neutrophilic disease was observed in 17/27 patients and was most frequent in infants. Neutrophilic disease of the upper respiratory tract, as well as cardiac neutrophilic disease, was only observed in infants, whereas other locations were similarly found in infants, young children and adolescents. In infants and young children, ND were associated with a large spectrum of general diseases, whereas in adolescents associations were limited to inflammatory bowel disease and Behçet's disease. CONCLUSIONS: Our study describes the concept of ND in paediatric patients and shows that they have some characteristics different from ND occurring in adults. ND occurring in infants can be associated with a large spectrum of general diseases. Occurrence of neutrophilic disease is frequent in children. Thus, ND occurring in young paediatric patients should incite clinicians to schedule complementary explorations in order to search for involvement of other organs and to rule out monogenetic autoinflammatory syndromes.

[Erythroderma revealing IPEX syndrome]. / Érythrodermie révélatrice d'un syndrome IPEX.

BACKGROUND: Primary immunodeficiencies are rare and frequently life-threatening conditions in the first year of life. They may present with isolated skin manifestations and the absence of other clinical signs may delay diagnosis and management of the disease. Herein we describe a case of IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome) that illustrates this situation. PATIENTS AND METHODS: A 2.5-month-old boy was seen with a psoriasiform eruption. Despite applications of topical steroids, skin lesions progressed to severe exfoliative ichtyosiform erythroderma. A skin biopsy showed keratinocyte necrosis with a dense, epidermotropic, lymphocytic CD8+ infiltrate. The infant presented increased serum IgE and eosinophilia. He developed an enteropathy with severe and profuse diarrhea, septicemia and hypovolemic shock that led to sudden cardiac arrest. DNA analysis revealed a mutation in the FOXP3 gene, confirming IPEX syndrome. A favorable outcome was achieved following allogeneic bone marrow transplant. DISCUSSION: IPEX syndrome is characterized by early secretory enteropathy with profuse diarrhea, dermatitis and diabetes mellitus. Onset usually occurs within the first weeks or months of life, and the natural course of the disease is often lethal. Cutaneous manifestations appear to be mostly eczematiform, psoriasiform or ichthyosiform. These may be the first sign of the disease and a common inflammatory skin disorder may be wrongly diagnosed. The severity of the lesions and their limited response to topical steroids should alert the clinician. CONCLUSION: The early onset of severe cutaneous manifestations with persistent lesions and poor response to topical steroids should lead to an early skin biopsy. If histopathological changes show a cytotoxic lymphocytic infiltrate with keratinocyte necrosis, a diagnosis of primary immunodeficiency must be considered enabling rapid intitation of specific management.

Peanut gastrointestinal delivery oral immunotherapy in adolescents: Results of the build-up phase of a randomized, double-blind, placebo-controlled trial (PITA study).

BACKGROUND: Oral immunotherapy to peanut is effective in desensitizing patients but has significant side effects including anaphylaxis and gastrointestinal symptoms. In most protocols, peanut is administered in a vehicle food. OBJECTIVE: In an exclusively adolescent population, we tested a new approach using sealed capsules of peanut (gastrointestinal delivery oral immunotherapy or GIDOIT) to bypass the upper gastrointestinal tract. The primary aim was to assess the efficacy of the oral build-up phase of GIDOIT and the secondary aim to analyse its safety. METHODS: Adolescents with a history of a clinical allergic reaction after peanut ingestion were included in a 2-armed, parallel-design, individually randomized, double-blind, placebo-controlled, multicentre trial after a positive double-blind placebo-controlled oral food challenge (DBPCFC1). A central randomization centre used computer-generated tables to allocate treatments. Peanut (or placebo) capsules were ingested daily over a period of 24 weeks with increments every 2 weeks from 2 to 400 mg of peanut protein (pp). Primary outcome was tolerance of 400 mg of pp at DBPCFC2. RESULTS: Thirty patients were included between September 2013 and May 2014. At DBPCFC2, unresponsiveness to 400 mg of pp was achieved in 17/21 peanut group patients (2 withdrawn patients) and 1/9 in the placebo group (Intention-to-treat analysis, P < .001, absolute difference = 0.7, 95%IC 0.43 0.96). Oropharyngeal symptoms were equally frequent in both groups. No dysphagia or other signs of eosinophilic oesophagitis occurred. Digestive adverse events (AE) were more frequent in the treated group (P = .02), but mild and without compliance issues. Only one severe advent event led to withdrawal in a patient who ingested twice the investigated treatment. Peanut-specific humoral immune responses were modulated. CONCLUSION: The GIDOIT protocol demonstrated clinical and immunological efficacy and had an acceptable level of safety with weak oropharyngeal symptoms, no dysphagia, mild digestive events and few severe systemic AE.

Non-invasive biological quantification of acute gastrointestinal graft-versus-host disease in children by plasma citrulline.

Clinical grading of GI involvement during acute GVHD remains a challenging issue, especially in children. Plasma citrulline, a non-protein amino acid selectively produced and released by enterocytes, is a suitable surrogate endpoint for small intestinal epithelial cell mass, irrespective of the underlying cause of cell loss. Children referred for allogeneic bone marrow transplantation who were free from chronic malabsorption or constitutional disease involving the GI tract were consecutively included in this prospective study. Plasma citrulline and albumin concentration was measured every week between day 7 and day 28 of BMT until resolution of the aGVHD or occurrence of chronic GVHD. In total, 31 children were included between 2008 and 2011. After a CR, citrulline levels fell to a minimum level on day 7 and then increased to reach the initial value on day 28. After day 28, plasma citrulline but not albumin was strongly linked to the occurrence of GI GVHD, the threshold being set at 10 µmol/L. The correlation with clinical grade of GI-aGVHD now needs to be assessed in larger populations. In pediatric patients, citrulline is valuable as a suitable non-invasive marker of GI involvement in acute GVHD.

Long-term red blood cell exchange in children with sickle cell disease: manual or automatic?

Little information is available on erythrocytapheresis in children with sickle cell disease, and no comparison has ever been made with manual exchanges in a long-term blood exchange program. We matched a historical cohort of five patients who received 60 erythrocytapheresis procedures with five who received 124 manual exchanges. Long-term erythrocytapheresis was feasible and well-tolerated even in children of low weight. In a long-term approach, automated exchanges were more efficient in maintaining a low HbS level, and exchanges could be spaced out. This approach appears especially useful in the cases where the HbS level must be maintained below 30%.

Disease evolution in systemic juvenile idiopathic arthritis: an international, observational cohort study through JIRcohort.

BACKGROUND: Systemic juvenile idiopathic arthritis (systemic JIA) is a severe disease with both systemic and joint inflammation. This study aims to identify predictors of disease evolution within the systemic JIA population enrolled in the Juvenile Inflammatory Rheumatism cohort (JIRcohort). METHODS: Observational patient cohort study with 201 recruited children from 4 countries (3 European, 1 North Africa) from 2005 until 2019, using retrospectively (2005-2015) and prospectively (2015-2019) routine care collected data. RESULTS: Sixty-five patients with complete follow-up data for 24 months after first diagnosis were classified as monophasic (n = 23), polyphasic (n = 6) or persistent group (n = 36) corresponding to their evolution (unique flare, recurrent flares, or persistent disease activity respectively). The patients of the persistent group were more likely to have an earlier disease onset, before the age of 6 (OR 2.57, 95%-CI 0.70-9.46), persistence of arthritis at 12-months post-diagnosis (OR 4.45, 95%-CI 0.58-34.20) and higher use of synthetic DMARD (sDMARD, OR 5.28, 95%-CI 1.39-20.01). Other variables like global assessment by physician and by patient and C Reactive Protein levels at 12-months post-diagnosis were assessed but without any predictive value after adjusting for confounding factors. CONCLUSIONS: Our results suggest that the earlier disease onset, the persistence of arthritis throughout the first year of disease evolution and the need of sDMARD might predict a persistent disease course.

Lumbar puncture in infants with urinary tract infection: Assessment of infant management in the emergency department.

BACKGROUND: Neonatal bacterial infections must be bacteriologically confirmed from laboratory samples to best adjust antibiotic therapy. Lumbar puncture (LP) has been recommended for infants younger than 1 month with suspected serious bacterial infection (SBI) to manage possible meningitis. However, the incidence of bacterial meningitis associated with other infections and particularly with urinary tract infections (UTIs) is low. Recourse to systematic LP may be less essential if infants have a UTI. We aimed (a) to determine the management and frequency of bacterial meningitis coexisting with a documented diagnosis of UTI in infants aged < 1 month who had an LP, and (b) to evaluate the management of infants in emergency admissions with suspected SBI while assessing antibiotic treatment. METHODS: We conducted a retrospective single-center study from January 2010 to April 2019 including all cases of neonatal bacterial infections, and collected data on the clinical, laboratory, and radiological features. RESULTS: In all, 409 infants were included in the study. Of these, 162 (39.6%) presented with a UTI and eight (2%) had bacterial meningitis. Of the infants diagnosed with UTI, 74.7% had an LP, of whom 34.7% experienced LP complications. No coexistence of UTI and bacterial meningitis was found among infants who had an LP and a documented UTI. CONCLUSION: Although not all infants had an LP and a urine culture at the same time, these results show that bacterial meningitis coexisting with a confirmed UTI diagnosis in infants is rare. Furthermore, LP can be traumatic in some cases and therefore its utility should be assessed according to the clinical context.

Evidence of a clinical response at one yr after reduced-intensity allogeneic hematopoietic stem cell transplantation in heavily pretreated adolescents with aggressive refractory Hodgkin's lymphoma.

We report results of RIC AHSCT in four adolescents with aggressive refractory HL. They all received three or four lines of therapy prior to RIC-AHSCT including autografts. At the time of RIC, they were in partial response except for one patient who had progressive chemoresistant disease. The conditioning regimen consisted of fludarabin, busulfan and ATG. They all had a matched related donor. The median follow-up was 12-16-month post-allograft. All patient transplants engrafted rapidly. The median time of hospitalization was 35 days. The median time to neutrophil recovery (>or=500/muL) was 19 days. All the patients were in complete donor chimerism at day 60. Four patients developed skin (grade

Four successful pregnancies in a patient with mucopolysaccharidosis type I treated by allogeneic bone marrow transplantation.

To date, little is known about the fertility of women suffering from mucopolysaccharidosis type I (MPS I). We report on a female patient with MPS I treated by allogeneic bone marrow transplantation (BMT) at the age of 4 years (after a conditioning regimen containing busulfan 16 mg/kg and cyclophosphamide 100 mg/kg) who had four successful pregnancies without any reproductive assistance. Clinical and biological examinations of the children were normal. On the basis of this case, we discuss the fertility counselling of female MPS I patients at the time of BMT.

Using health promotion outcomes in formative evaluation studies to predict success factors in interventions: an application to an intervention for promoting physical activity in Dutch children (JUMP-in).

JUMP-in is a systematically developed intervention aimed at promoting physical activity among primary school children. It is a joint project involving different authorities and entails six school-based programme components. Measuring effects of such an intervention is a complex challenge. A common problem is the lack of valid instruments to measure physical activity and its determinants. In addition, it usually takes years to find improvements in physical activity and related constructs like weight and fitness, or even in causal factors. For this reason different authors advocate for the establishment of 'health promotion outcomes'; (i) health literacy, (ii) social action and influence and (iii) healthy public policy and organizational practice. It is presumed that these health promotion outcomes lead to changes in determinants, behaviour and finally in health. Insight in these health promotion outcomes and information about input and through-put are important in discussing the impact and output. The formative evaluation study of the JUMP-in pilot shows the health promotion outcomes of the intervention. The health promotion outcomes 'social action and influence' and 'healthy public policy and organizational practices' were found to be positive. By measuring the presence of the conditions to achieve 'health literacy', it became clear that more attention must be paid to implementation in the future. Based on the health promotion outcomes, we expect that JUMP-in will be an effective intervention in the future.

[Implementation of quality assurance program ISO 9001 in a department of paediatric oncology]. / Mise en place d'un système d'assurance qualité ISO 9001 en cancérologie pédiatrique.

OBJECTIVE: Our objective was to improve the organization and management of care facilities for children suffering from cancer or leukaemia and to be aligned with the legislation in force in France. METHODS: Our report is on the successive steps for the implementation of a quality assurance system, methods used, motivations, cost, difficulties encountered as well as the advantages obtained. In the Regional Centre for Paediatric Oncology (CRCP) at the CHU in Clermont-Ferrand, we launched a quality programme based on ISO9001/2000 standards. The implementation of the quality assurance system was conducted as a research project and an established medical project with the support of the Management Team. The mission was divided into several "processes", an approach consisting of considering the clinical service in terms of flow and successions of transformations (reception, care, support, accompaniment, etc.) which produce added-value (services and products adapted to the needs of the "customers": children, families, correspondents). RESULTS: We singled out ten physical processes or "job specializations" such as "diagnosis", "care" or "project for the child". The cartography which is the systematic representation of the processes and the interactions between them made it possible to draw up a global vision of the CRCP "care" activity. CONCLUSION: The ISO9001/2000 standard is a tool designed to help organization and management. The benefit obtained in implementing it in a clinic was perceived in organisational terms and lead to a true team spirit, a standardization of the professional practices and the enhancement of the role of each person. The advantages appear at three levels: the child and his/her family, the medical and paramedical teams, and the administrative supervisory bodies.

[Transverse reductional anomaly and atypical fibrodysplasia ossificans progressiva: A case diagnosed late]. / Anomalie réductionnelle transverse et fibrodysplasie ossifiante progressive atypique, à propos d'un cas de diagnostic tardif.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by the association of congenital bone abnormalities and extraskeletal ossification flare-ups occurring in muscles and fasciae. Early diagnosis is important to prevent ossification flare-ups, but some atypical presentations can lead to errors in diagnosis and therefore delay. Here, we report on a case of an atypical presentation of FOP in a girl, in whom prominent transverse reductional abnormalities delayed diagnosis. The patient developed extraskeletal ossifications and progressive fibrosis that led to motor restrictions. Since early diagnosis is important, we discuss the clinical presentations of FOP and the differential diagnoses.

Intravenous immunoglobulins for severe gastrointestinal involvement in pediatric Henoch-Schönlein purpura: A French retrospective study.

OBJECTIVE: Severe gastrointestinal involvement of Henoch-Schönlein purpura (HSP) is rare but potentially life-threatening. Management of severe gastrointestinal involvement in HSP is not codified. Symptomatic care and steroids are a first-line therapy. Nonsteroidal immunomodulatory therapies have been anecdotally used to treat steroid-refractory forms. The aim of this study was to describe the outcome of patients with severe gastrointestinal involvement of HSP who required nonsteroidal immunomodulatory therapy. METHODS: A French retrospective case series study was conducted. Pediatric consultants at 31 French academic pediatric centers were contacted. Patients were identified from memory or via an informatics diagnosis-related code system. Clinical, paraclinical, and therapeutic data were collected. RESULTS: Twenty-nine responding centers provided nine cases, one of which was excluded. Five boys and three girls, aged 3-15years (median: 5.5years) from seven centers were included. Severe gastrointestinal involvement of HSP mainly included intense pain, digestive bleeding, and protein-losing enteropathy. All children had been treated with steroids at first line and intravenous immunoglobulins (IVIg) at second line. Six out of eight showed a complete response to IVIg within 7days and two out of eight had a partial response. Two out of eight relapsed with less severe gastrointestinal involvement requiring a second dose of IVIg and they did not relapse thereafter. Tolerance was good, but two out of eight developed high proteinuria on the day following IVIg infusion. CONCLUSION: Although a possible link with a flare-up of proteinuria needs to be addressed, IVIg appears to be a good candidate for treatment of severe gastrointestinal involvement of HSP.

[Gordon syndrome: The importance of measuring blood pressure in children]. / Syndrome de Gordon : de l'importance de mesurer la pression artérielle chez l'enfant.

Gordon's syndrome, or type II pseudo-hypoaldosteronism, is a rare cause of arterial hypertension in children. However, it is important to diagnose this syndrome because of the spectacular efficacy of thiazide diuretics. The typical clinical picture of Gordon syndrome includes, apart from arterial hypertension and dyskaliemia, hyperchloremia metabolic acidosis, hypercalciuria, a low rate of renin, and most frequently, a normal or high rate of aldosterone. Dental abnormalities and growth retardation can also be associated. In most cases, it is inherited in an autosomal dominant pattern. We report on a 7-year-old girl who was discovered with arterial hypertension during a consultation for chronic diarrhea. The association of growth retardation, hyperkaliemia, and metabolic acidosis oriented the diagnosis. Starting a thiazide diuretic helped control the arterial hypertension and the kaliemia in a spectacular manner. The genetic analysis proved the existence of a splice mutation on exon 9 of the CUL3 gene coding for cullin 3. This mutation is de novo.

[Pedagogic focus-group in pediatrics]. / Initiation à la pédagogie narrative en pédiatrie : le focus-groupe pédagogique.

AIM: To assess a new behavioral teaching technique called "focus group pedagogy" (FGP), which consists in a three-step meeting between sick children's parents and medical students (first with students alone, then with parents and students together, then with students alone). METHODS: This qualitative research ran two sessions (each totaling four to six parents and six students) in which parents were questioned on four main themes: their knowledge of the medical hierarchy, their ability to identify the people in the hospital, their communication with medical staff, and the overall care delivered to their children. A thematic analysis of the verbatim transcript was performed. RESULTS: In the FGP sessions, medical students voiced opinions on their degree of insertion in the medical and paramedical staff, and reported their presence as ambiguous, between care and learning. Parents voiced their experience of their child's hospital stay but also their wider conception of the parent/patient-physician relationship based on their parent-of-patient/parent-as-patient experiences. The meeting of parents and students highlighted divergent narratives on relationships with caregivers, communication, attitudes, knowledge, and competencies. This approach made it possible to hear and learn the point of view "from the other side," which proved beneficial for students, session leaders, and the care unit organization alike. CONCLUSION: FGP is a novel and easy way to discover diverse narratives and the technique is feasible and beneficial in pediatric settings.

Hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: experience of the French neutropenia registry.

Our objective was to study the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for Shwachman-Diamond Syndrome (SDS). Among 71 SDS patients included in the French Severe Chronic Neutropenia Registry, 10 received HSCT between 1987 and 2004 in five institutions. The indications were bone marrow failure in five cases, and myelodysplastic syndrome (MDS) or leukemia in five cases. The median follow-up of patients who survived without relapse is 6.9 years (3.1-16.8 years). The conditioning regimen consisted of a busulfan-cyclophosphamide combination (n=6) or total body irradiation plus chemotherapy (n=4). Six patients received stem cells from unrelated donors and four from identical siblings. Engraftment was complete in eight patients and unassessable in two patients. These latter two patients died of infections 32 and 36 days after HSCT, with grade IV graft-versus-host disease and multiorgan dysfunction. A third patient died from an acute respiratory distress syndrome 17 months after HSCT with progressive granulocytic sarcoma. One patient had an MDS relapse 4 months after HSCT and died 10 months later. The overall 5-year event-free survival rate is 60+/-15%. We conclude that HSCT is feasible for patients with SDS who develop bone marrow failure or malignant transformation.

[Adrenal hypoplasia congenita: four new cases in children]. / Hypoplasie congénitale des surrénales : à propos de quatre observations.

Adrenal hypoplasia congenita (AHC) is an extremely uncommon disease of early onset. This condition can be lethal in the absence of adapted treatment. Some of these diseases are related to changes in the gene DAX1 that encodes a member of the superfamily of hormone nuclear receptors. It is a transcriptional repressor that is central in the morphogenesis of the adrenals and the gonadic differentiation. Here we report on four cases of X- linked AHC. In the first two familial cases, mutations were identified and mothers were heterozygotes. Abnormally low levels of estriol were evidenced during the pregnancy leading to an early diagnosis and adapted care of the affected male neonates. These children are doing well with a 21-and 20 months follow-up with hormone replacement at the present time. The two last cases corresponded to a contiguous gene syndrome associating AHC to glycerol-kinase deficiency that was revealed respectively at six days and seven years of age by acute adrenal insufficiency.

Randomized trial with Poly A-Poly U as adjuvant therapy complementing surgery in patients with breast cancer: in vitro study of cellular immunity.

The immunologic reactivity of patients with initially operable breast cancer was measured by the leukocyte migration inhibition test using autologous tumor extract (T), autologous serum (S), and a combination of both (T + S). These patients formed part of a randomized clinical trial comparing, on the one hand, conventional treatment and, on the other, conventional treatment complemented by injections of poly A-poly U. A sequential study was carried out on 159 patients, testing them 7 days, 2 months, 4 months, and 1 year after the operation. Statistical comparisons revealed no significant difference in the reaction of the two groups. In addition, no significant differences were found between those with lymph node involvement and those without. Radiotherapy given to those with lymph node involvement did not significantly change their reactions. We were able to show that the percentage of patients with a positive leukocyte migration inhibition test (LMIT) increases regularly and significantly with time. This study confirmed the presence in some autologous serum of a synergistic factor (SS factor) which increased the inhibition of migration of leukocytes by autologous tumor extract. This factor was found in 18 patients, equally divided between both therapeutic groups. In the group with SS factor, the percentage with lymph node involvement appeared greater (83% compared with 68% among those patients who had no SS factor), and the incidence of metastases was also increased (44% compared with 21%). This factor seemed to indicate a bad prognosis. However, there was a difference in the results between the two therapeutic groups in patients with the synergistic factor. Of nine patients undergoing conventional treatment, six had devleoped metastases, whereas only two out of the nine patients who also poly A-poly U developed metastases. The same trend was observed in the whole trial population.