[Health status and quality of life in ß-thalassemia adults in Marseille, France]. / État de santé et qualité de vie des patients ß-thalassémiques adultes à Marseille, France.

INTRODUCTION: The life expectancy of ß-thalassemia patients has increased over the last 20 years. In this study, we evaluated the current health status and quality of life of these patients managed in a reference center in Marseille. METHODS: This is a single-center, descriptive study conducted between June and August 2019 in patients over 18 years of age with ß-thalassemia major or intermedia. Clinical and paraclinical data were collected retrospectively and the SF-36 health survey questionnaire was proposed to each patient. RESULTS: 43 of 64 selected patients were included and divided into 2 groups: 35 patients with transfusion-dependent ß-thalassemia and 8 patients with non-transfusion-dependent ß-thalassemia. Liver iron overload is the most frequent complication, present in 80% of transfusion-dependent and 62.5% of non-transfusion-dependent patients. Cardiac iron overload is present only in the transfusion dependent ß-thalassemia group (20%). Hypogonadotropic hypogonadism remains the most common endocrine disorder (41.9%) followed by osteoporosis (37.2%). Among the 31 patients who completed the SF-36 questionnaire, physical and mental quality of life scores were lowered in transfusion dependent (respectively 42.7 and 46.8) as in non-transfusion-dependent patients (respectively 43.8 and 28.9). CONCLUSION: Despite an improvement in medical care, our patients with ß-thalassemia show an alteration in their quality of life that will need to be characterized in the entire French cohort.

[Biological diagnosis of iron deficiency in children]. / Diagnostic biologique de la carence martiale chez l'enfant.

Measurement of serum ferritin (SF) is currently the laboratory test recommended for diagnosing iron deficiency. In the absence of an associated disease, a low SF value is an early and highly specific indicator of iron deficiency. The WHO criteria proposed to define depleted storage iron are 12µg/L for children under 5 years and 15µg/L for those over 5 years. A higher threshold of 30µg/L is used in the presence of infection or inflammation. Iron deficiency anemia, with typical low mean corpuscular volume and mean corpuscular hemoglobin, is only present at the end stage of iron deficiency. Other diagnostic tests for iron deficiency including iron parameters (low serum iron, increased total iron-binding capacity, low transferrin saturation) and erythrocyte traits (low mean corpuscular volume, increased zinc protoporphyrin) provide little additional diagnostic value over SF. In children, serum soluble transferrin receptor (sTfR) has been reported to be a sensitive indicator of iron deficiency and is relatively unaffected by inflammation. On the other hand, sTfR is directly related to extent of erythroid activity and not commonly used in clinical practice. In population surveys, approaches based on combinations of markers have been explored to improve the specificity and sensitivity of diagnostic. In addition to Hb value determination, a combination of parameters (among transferrin saturation, zinc protoporphyrin, mean corpuscular volume or serum ferritin) was generally used to assess iron deficiency. More recently sTfR/ ferritin index were evaluated, sTfR in conjunction with SF allowing to better distinguishing iron deficiency from inflammatory anemia. Also, hepcidin measurements appeared an interesting marker for diagnosing iron deficiency and identifying individuals in need of iron supplementation in populations where inflammatory or infectious diseases are frequently encountered. Reticulocyte Hb content (CHr) determination is an early parameter of iron deficiency erythropoiesis. CHr can be measured with several automated hematology analyzers and so, used for individual's iron status assessment. In addition to Hb concentration determination, individual's iron status is commonly assessed in the pediatric clinical practice by the SF measurement accompanied by the determination of C-reactive protein for detection of a simultaneous acute infection and/or inflammation.

[Current management of thalassemia intermedia]. / Prise en charge actuelle des thalassémies intermédiaires.

Thalassemia intermedia is a clinical entity where anemia is mild or moderate, requiring no or occasional transfusion. Non-transfusion-dependent thalassemia encompasses 3 main clinical forms: beta-thalassemia intermedia, hemoglobin E/beta-thalassemia and alpha-thalassemia intermedia (HbH disease). Clinical severity of thalassemia intermedia increases with age, with more severe anemia and more frequent complications such as extramedullary hematopoiesis and iron overload mainly related to increased intestinal absorption. Numerous adverse events including pulmonary hypertension and hypercoagulability have been associated with splenectomy, often performed in thalassemia intermedia patients. The potential preventive benefit of transfusion and chelation therapies on the occurrence of numerous complications supports the strategy of an earlier therapeutic intervention. Increasing knowledge about pathophysiological mechanisms involved in thalassemia erythropoiesis and related iron overload is currently translating in novel therapeutic approaches.

MRI monitoring of myocardial iron overload: use of cardiac MRI combined with hepatic MRI in a cohort of multi-transfused patients with thalassaemia.

PURPOSE: We report the results of combining cardiac and hepatic MRI in the same examination to monitor 48 multi-transfused patients presenting iron overload secondary to their transfusions. This cardiac MRI technique uses acquisition sequences and calculation software that are readily available for 1.5 T systems, and it has been validated to screen for patients at risk of cardiac complications who present myocardial iron overload (T2*<20milliseconds). PATIENTS AND METHODS: A total of 176 combined MRI examinations were performed between May 2006 and January 2012 in 48 patients who had received transfusions due to thalassaemia. This monocentric retrospective study brings together all of the imaging examinations carried out. RESULTS: There was a positive correlation between the cardiac T2* values and left ventricular ejection fraction, which were measured in the same examination. At the first assessment 23/48 patients had a T2*<20ms. These patients showed a significant improvement in cardiac T2* over time while their iron chelation therapy was being intensified. CONCLUSION: This study validates the application of the cardiac MRI technique used to monitor cardiac iron overload in patients who have undergone multiple transfusions.

Iron overload of hematological origin: validation of a screening procedure for cardiac overload by MRI in routine clinical practice.

PURPOSE: Screening for cardiac iron overload is generally done by magnetic resonance imaging (MRI) and demonstrated by a shortening of the myocardial T2* below 20 ms at 1.5 Tesla. This measurement was validated with a specific sequence and the CMRTools(®) calculation software (reference technique). The objective of this study was to validate the use of sequences and software programs that are available in routine clinical practice to screen for iron overload. MATERIAL AND METHODS: First, a phantom of 11 tubes with a T2* between 4 and 33 ms was tested at three sites that had MRI machines of different brands. Second, the myocardial T2* values of 75 patients were measured in routine clinical practice using two methods. The first method used the reference sequence specially installed in the machines associated with the CMRTool software. The second method used the standard acquisition sequences available in the machines followed by calculation on a computer spreadsheet. RESULTS: In the phantom, the mean of the differences in T2* between each machine was 0.6 ms. Thirteen patients had a lowered T2* value with the reference technique. Three cases were poorly classified using the routine technique and corresponded with false positives of low overload (T2* between 18 and 20 ms). CONCLUSION: Screening for myocardial iron overload can be done by MRI by using sequences and calculation software available in routine clinical practice during the same examination as the one for the evaluation of hepatic iron overload.

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%.

Height growth during adolescence and final height after haematopoietic SCT for childhood acute leukaemia: the impact of a conditioning regimen with BU or TBI.

We compared the impact of a conditioning regimen with BU (n=16) or fractionated TBI (n=42) on height growth during adolescence and final height (FH), in 58 adults transplanted for acute leukaemia before adolescence (younger than 9 for girls and 11 for boys, and prepubertal). Heights were measured at three key periods, that is, transplantation, before adolescence, and FH, and compared using height standard deviation score (SDS) and cumulative change in SDS. The influence of the conditioning regimen was assessed using multiple linear regression and adjusting for gender, central nervous system irradiation, age and leukaemia status at transplant and type of transplantation. Overall mean height SDS was near normal at transplantation and before adolescence (0.2+/-0.1 and -0.2+/-0.1, respectively), but decreased to -1.6+/-0.1 at FH. There were significant differences between the TBI and BU groups when comparing FH SDS (-1.8+/-0.2 vs -0.8+/-0.2, P=0.001), mean change in height SDS from transplantation to FH (-2+/-0.1 vs -1.1+/-0.2, P=0.002) and mean change in height SDS during adolescence (-1.6+/-0.1 vs -0.7+/-0.2, P=0.003). We conclude that preparations involving BU, although less toxic than TBI-containing regimens, also have adverse effects on growth, predominantly during adolescence.

[Hereditary spherocytosis: guidelines for the diagnosis and management in children]. / Sphérocytose héréditaire: recommandations pour le diagnostic et la prise en charge chez l'enfant.

Hereditary spherocytosis (HS) is the commonest inherited disorder of the erythrocyte membrane in Northern Europe and North America. It is marked by a regenerative anemia which varies widely from asymptomatic patients to severe hemolysis. In 75% of HS patients, inheritance is autosomal dominant. The diagnosis of HS is easily made when there are a family history, hemolytic anemia, reticulocytosis, spherocytes and increased hyperdense cells. Specialized testing to clarify the nature of membrane disorder is required when the film appearance is atypical without a positive family history, in the absence of a family history, in the newborn and before the splenectomy, to rule out the stomatocytosis which is contraindicated. The indication for splenectomy is dependent on the degree of anemia and its clinical manifestation.

Health status and quality of life in long-term survivors of childhood leukaemia: the impact of haematopoietic stem cell transplantation.

We compared late side effects and quality of life (QoL) in 430 survivors of childhood acute leukaemia based on whether they had undergone haematopoietic cell transplantation (n=142) or not (n=288). Mean age was 18.2 years and mean follow-up duration was 11.9 years. Multivariate logistic regression analyses were performed to compare the risk of each type of late effect in the two groups. Based on age, VSP-A or SF36 questionnaires were used to assess QoL. For each QoL dimension, multiple linear regression was done to construct models of association with the treatment group. Transplanted patients experienced more side effects, including height growth failure, gonadal dysfunction, hypothyroidism and cataract. Children and adolescents in the two treatment groups reported similar QoL levels for almost all dimensions except a better perception of school work by young transplanted children and more difficulties in relating to the medical staff for transplanted adolescents. In adults, two differences in physical domain of QoL were detected but the calculated effect sizes were less than 0.2 in each case, suggesting an uncertain clinical significance. In spite of a higher risk of physical adverse events in the transplanted group, very few clinically significant differences in QoL are detectable.

CD34(+) progenitors are reproducibly recovered in thawed umbilical grafts, and positively influence haematopoietic reconstitution after transplantation.

Cord blood (CB) units are increasingly used for allogeneic transplantation. Cell dose, a major factor for CB selection, is evaluated before freezing by each CB bank, using various techniques. This may introduce variability and affect the prediction of cell recovery after thawing, or haematopoietic reconstitution. Forty-two children were transplanted at the same institution with unrelated CB units. All units were thawed and evaluated at the same cell therapy facility, using standard procedures. We investigated: (i) factors that affect cell loss after thawing, and (ii) the importance of CD34(+) cell doses. Prefreeze and post-thaw CD34(+) cell doses were statistically correlated, thus suggesting that variability in numeration techniques used by different CB banks does not compromise the biological and clinical value of these figures. CD34(+) cell recovery appeared to be correlated with the absolute number of CD34(+) cells per frozen bag. Infused CD34(+) is the cell dose that better correlates with platelet reconstitution delay; in addition, when using a quartile comparison, haematopoietic recovery appeared to be related with prefreeze and post-thaw CD34(+) cell doses. We conclude that enumeration of CD34(+) cells in CB units is of biological significance, and may help select CB units and identify patients at risk of delayed recovery.

[Evans' syndrome: a retrospective study from the ship (French Society of Pediatric Hematology and Immunology) (36 cases)]. / Syndrome d'Evans: étude rétrospective de la société d'hématologie et d'immunologie pédiatrique (36 cas).

UNLABELLED: Evans' Syndrome (ES) is defined as the combination of immune thrombocytopenia (ITP) and autoimmune haemolytic anemia (AIHA), in the absence of any known underlying etiology. Pathophysiology, epidemiology and outcome remain unclear. POPULATION: Thirty-six children (20 male, 16 female), who were diagnosed in the SHIP french centres (Société d'hématologie et d'immunologie pédiatrique) between 1990 and 2002 with ES, were included in this retrospective study. RESULTS: Median age at diagnosis was 4 years. In 21 children, ES occurred in the setting of consanguinity, family history of autoimmune/inflammatory disease, associated autoimmune disorder or immunoregulatory abnormalities (serum imunoglobulins, peripheral blood lymphocytes subsets, low level of the C3-C4 complement components, nuclear antibodies). Several successive treatments were used in this serie (median: 3, range: 0-10) including corticosteroid therapy (35/36), intravenous immunoglobulins (32/36), immunosuppressive agents (14/36), splenectomy (9/36) and anti CD 20 monoclonal antibodies (6/36). Patients with a low level of serum immunoglobulins were more often non-responders to corticosteroidtherapy/intravenous immunoglobulins and required more frequently further therapy (P=0.03). Three patients died (intracranial bleeding, N=2, Guillain-Barre syndrome; N=1). CONCLUSION: ES was a severe, life-threatening disease, requiring aggressive immunosuppressive therapy in as many as half the patients. Our forthcoming study aims to (i) describe homogeneously-studied and prospectively-analysed cohort of childhood ES, (ii) separate ES from specific immune deficiency (especially fas gene mutations), generalised autoimmune/inflammatory disorders and genetic diseases, (iii) identify well-defined ES subsets, (iv) establish prognostic factors and optimal treatment within these subsets.

Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit--multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group.

From 1989 to 1998, 341 children were included in the French multicentric LAME (Leucémie Aiguë Myéloblastique Enfant) trials. A total of 309 children were registered in the LAME 89/91 protocol. This intensive regimen included an induction phase (mitoxantrone plus cytarabine), two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine; 276 (90%) achieved a CR. The 5-year overall survival (OS) and event-free survival (EFS) were 60+/-4 and 48+/-4%, respectively. From 1997, timed-sequencing of the LAME SP induction chemotherapy led to an unacceptable frequency of consolidation delay; future improvements are unlikely to come from further increases in intensity. The role of allogenic bone-marrow transplantation from an HLA-identical sibling in CR1 was examined. The disease-free survival (DFS) was 52+/-4% for non-allografted patients and 57+/-7% for allografted patients (P=NS); a better OS for allografted patients was shown and could be related either to allo-BMT early in CR1 or to a second allo-BMT in CR2. For the complete responders after consolidation therapy, the 5-year OS was significantly better in patients randomized for no maintenance therapy (MT-) than in patients randomized for MT (77.6+/-8 vs 59+/-8%; P=0.05), while the 5-year DFS was not significantly different. Exposure to low-dose MT might contribute to clinical drug resistance and treatment failure in relapsing patients.

[When to initiate antiretroviral therapy in HIV-infected children?]. / Infection à VIH de l'enfant: quand débuter le traitement antirétroviral?

Administration of highly active antiretroviral treatment (HAART) has led in the developed world to a dramatic reduction in the incidence of HIV related pediatric mortality. HAART is now the standard-of-care therapy in infected children but the occurrence of short- and long-term drug-related toxic effects and emergence of drug-resistant viral variants temper its success. In children, both CD4 cell percent and viral load have independent predictive value for disease progression, CD4 cell being the stronger predictor of AIDS and death. Concerning children aged 12 months or oder current French recommendations for immediate therapy are based on the presence of clinical symptoms (of categories B or C) or the occurrence of a severe immunodeficiency (CD4 cell percent < 15%). In infants, risk of disease progression is higher and the viral load and CD4 percent are less reliable markers. HAART should theoretically be initiated in all infants in order to prevent HIV encephalopathy and early death. However, viral failure under HAART is often encountered in children less than 12 months because of high levels of replication as well as limited data on pharmacokinetics and drug dosing. A possible alternative approach for infants without risk factor for early progression is to defer HAART under close mentoring.

[Thyroid dysfunction after haematopoietic stem cell transplantation during childhood]. / Complications thyroïdiennes après greffes de cellules souches hématopoïétiques dans l'enfance.

UNLABELLED: To evaluate the percentage and risk factors of thyroid dysfunction in 79 children who underwent bone marrow transplantation in a single centre. PATIENTS AND METHODS: The mean age of the cohort was 6.8 and mean follow-up 5.5 years. The 79 patients were divided in two groups according to the pretransplant conditioning regimen: fractionated total body irradiation (TBI)(N=54), chemotherapy with Busulphan (N=25). Thyroid function was evaluated by thyroid-stimulating hormone (TSH) and free thyroxine (fT4) tests. Overt hypothyroidism was defined by low fT4 blood levels and TSH > 4 mU/l, and compensated hypothyroidism by normal fT4 index and TSH >4 mU/L. RESULTS: The six-year probability of hypothyroidism was 36 +/-6% for the whole group of 79 patients, 49 +/-8% after TBI and 9 +/-6% in the Busulphan group (P <0.001). Neither gender, nor primary disease, nor presence of graft versus host disease were found to be statistically significant for occurrence of hypothyroidism in the TBI group. However, a younger age seemed to influence statistically the 6-year probability of hypothyroidism in the TBI group: 59 +/-9% if age <7.7 years versus 34 +/-13% if age >7.7 years (P =0.02). CONCLUSION: A careful follow-up of thyroid function is recommended even without TBI conditioning regimen. Young age as a potential risk factor of hypothyroidism has never been described and needs to be studied in a larger cohort.

Lymphocyte-predominant Hodgkin's lymphoma in children: therapeutic abstention after initial lymph node resection--a Study of the French Society of Pediatric Oncology.

PURPOSE: To clarify treatment strategy for lymphocyte-predominant Hodgkin's lymphoma (LPHL), the French Society of Pediatric Oncology initiated a prospective, nonrandomized study in 1988. Patients received either standard treatment for Hodgkin's lymphoma or were not treated beyond initial adenectomy. PATIENTS AND METHODS: From 1988 to 1998, 27 patients were available for study. Twenty-four patients were male, and median age was 10 years (range, 4 to 16 years). Twenty-two, two, and three patients had stage I, II, and III disease, respectively. Thirteen patients (stage I, n = 11; stage III, n = 2) received no further treatment after initial surgical adenectomy (SA). Fourteen patients received combined treatment (CT; n = 10), involved-field radiotherapy alone (n = 1), or chemotherapy alone (n = 3). The two groups were comparable for clinical status, treatment, and follow-up. RESULTS: Twenty-three of 27 patients achieved complete remission (CR). With a median follow-up time of 70 months (range, 32 to 214 months), overall survival to date is 100%, and overall event-free survival (EFS) is 69% +/- 10% (SA, 42% +/- 16%; CT, 90% +/- 8.6%; P <.04). If we considered only the patients in CR after initial surgery (n = 12), EFS was no longer significantly different between the two groups. Patients with residual mass after initial surgery (n = 15) had worse EFS if they did not receive complementary treatment (P <.05). CONCLUSION: Although based on a small number of patients, our study showed that (1). no further therapy is a valid therapeutic approach in LPHL patient in CR after initial lymph node resection, and (2). complementary treatment diminishes relapse frequency but has no impact on survival.

[Severe upper airway obstruction in infectious mononucleosis: a life emergency]. / L'obstruction sévère des voies aériennes supérieures au cours de la mononucléose infectieuse: une urgence vitale.

BACKGROUND: Upper airway obstruction can represent a severe, life-threatening complication of infectious mononucleosis. We report a rare case of airway obstruction in a child with infectious mononucleosis associated with herpes virus infection, and we discuss management strategy that can be proposed in such cases. CASE REPORT: A 9-year-old girl was hospitalised in intensive care unit for obstructive dyspnea during infectious mononucleosis. Despite five days of corticosteroids and tracheal intubation, persistent pharyngo-tonsillar tumefaction led us to perform a surgical adenotonsillectomy. This latter treatment allowed immediate tracheal extubation and a rapid recovery. Histology showed a herpes virus infection associated with infectious mononucleosis. CONCLUSION: Maintaining airway opening in infectious mononucleosis needs sometimes to use instrumental interventions: nasal trumpet, endotracheal intubation, even tracheostomy. Early tonsilloadenoidectomy may relieve airway obstruction and allow a rapid recovery in the most severe cases. Airway obstruction in infectious mononucleosis may be aggravated by concomitant herpes virus infection that should be searched for in this situation, in order to adapt the treatment.