M. de Montalembert

Management of chronic viral hepatitis in patients with thalassemia: recommendations from an international panel.

Chelation therapy with new drugs prevents cardiac damage and improves the survival of thalassemia patients. Liver diseases have emerged as a critical clinical issue. Chronic liver diseases play an important role in the prognosis of thalassemia patients because of the high frequency of viral infections and important role of the liver in regulating iron metabolism. Accurate assessment of liver iron overload is required to tailor iron chelation therapy. The diagnosis of hepatitis B virus- or hepatitis C virus-related chronic hepatitis is required to detect patients who have a high risk of developing liver complications and who may benefit by antiviral therapy. Moreover, clinical management of chronic liver disease in thalassemia patients is a team management issue requiring a multidisciplinary approach. The purposes of this paper are to summarize the knowledge on the epidemiology and the risks of transmission of viral infections, to analyze invasive and noninvasive methods for the diagnosis of chronic liver disease, to report the knowledge on clinical course of chronic viral hepatitis, and to suggest the management of antiviral therapy in thalassemia patients with chronic hepatitis B or C virus or cirrhosis.

Preliminary report of a toxicity study of hydroxyurea in sickle cell disease

AIM To evaluate the tolerance of hydroxyurea in children affected with sickle cell disease. DESIGN Questionnaire study of French physicians likely to treat patients with sickle cell disease. Data were collected on 101 children with sickle cell disease, treated for a median of 22 months, 36 of whom were treated for more than three years. 13 children were younger than 5 years of age at inclusion. RESULTS Hydroxyurea was stopped for medical reasons in 11 patients: 6 failures, 1 pregnancy, 1 cutaneous rash, 1 leg ulcer, 1 lupus. Acute lymphoblastic leukaemia occurred in a girl treated for 1.5 months with hydroxyurea, this short interval arguing against a causative association. One 17 year old boy had paraparesis after 8 years of treatment. CONCLUSIONS No major short or medium term toxicity was related to hydroxyurea in this cohort of 101 children. However, the number of children treated for more than 3 years is too few to make firm conclusions on the long term tolerance of this drug.

Osteopenia and vitamin D deficiency in children with sickle cell disease.

Objectives:  To assess the prevalence in children with sickle cell disease of low bone mineral density (BMD), a feature found in up to 82% of adults but not well known in children.

Myocardial ischaemia in children with sickle cell disease

Background: The heart may be involved in children affected with sickle cell disease (SCD) via several mechanisms. Principally, chronic anaemia increases cardiac output and may cause left ventricular enlargement and cardiac insufficiency. Aims: To investigate whether the heart also suffers from ischaemia in SCD, as has already been shown for other organs (bone, brain, etc), and to look for risk factors predisposing to this complication. Methods: Twenty two children with SCD, and chest pain or ECG or echocardiographic signs (left ventricle dilation or hypokinesis) suggesting myocardial ischaemia were subjected to thallium-201 (201Tl) single photon emission computed tomography (SPECT). Results: Eight children had a normal SPECT, 14 an abnormal one. Myocardial perfusion defects were reversible in nine, fixed in five. Patients with perfusion defects tended to be older and have more severe disease. Five had had cardiac symptoms (episodes of cardiac failure in three, ventricular fibrillation in one, angina in one). Myocardial perfusion was reassessed after six months of hydroxyurea treatment in three patients, and was found to be improved. Conclusions: Myocardial perfusion defects are present in children with SCD and may be demonstrated using SPECT. Hydroxyurea improved perfusion in three patients.

Partial splenectomy in homozygous beta thalassaemia.

Partial splenectomy was performed on 30 patients with homozygous beta thalassaemia to reduce blood requirements and to avoid the risk of overwhelming postsplenectomy infections; 24 patients had thalassaemia major and six thalassaemia intermedia. Five patients received a high transfusion regimen before and after surgery and 25 a lower one. Follow up after surgery ranged from one to four years. Partial splenectomy improved the long term haematological state in the six patients with thalassaemia intermedia. Recurrence of hypersplenism occurred in nine of the 24 patients with thalassaemia major, however, and complete splenectomy was required. Serum IgM concentrations were not significantly modified by surgery. The mean (SD) residual spleen after surgery was 4.45 (2.36) cm measured by scintigraphy. No severe infections occurred after surgery; however, most patients were routinely treated with phenoxymethylpenicillin and the protective effect of the remaining spleen could not be exactly determined. Because of the possibility of recurrence of hypersplenism, routine partial splenectomy when splenectomy is needed in thalassaemia major is not advised, except in children under 5 years whose risk of overwhelming postsplenectomy infection is greatest.

Partial splenectomy in sickle cell syndromes.

Partial splenectomy was carried out in four children with homozygous sickle cell disease and eight children with sickle cell beta thalassaemia. It was performed in order to preserve splenic contribution to the host defence against infections while suppressing hypersplenism or the risk of recurrence of acute splenic sequestration. Indications for this surgical operation were acute splenic sequestration (n = 1), hypersplenism (n = 5), and acute splenic sequestration and hypersplenism (n = 6). Surgery was uneventful in 11 patients. A significant reduction of blood requirements and a significant decrease of the number of hospitalisations/patient/year were observed after splenectomy. No recurrence of hypersplenism or acute splenic sequestration occurred and no severe infection was noticed during the follow up period after surgery (mean (SD) 4.2 (2.8) years; range 6 months-7 years). Mean haemoglobin concentration and leucocyte and platelet counts increased after surgery. The benefit of partial splenectomy compared with total splenectomy to treat acute splenic sequestration or hypersplenism in sickle cell disease is discussed.

Cerebrovascular accidents in sickle cell disease. Risk factors and blood transfusion influence

This study presents a series of 34 sickle cell patients with one or more cerebrovascular accidents (CVA). Risk factors were studied in a subgroup of 19 patients whose clinical and biological characteristics were compared to those of a group of 444 sickle cell patients without CVA. The only risk factor discovered was a past history of purulent meningitis, which was significantly more frequent in sickle cell patients than in those without CVA (P<0.0001). No biological or radiological factor affecting the risk of recurrence was found. The risk of recurrence, neurological defects or death after subsequent CVA justify long-term transfusion treatment in patients presenting with a second CVA. However our study shows that 10 patients who were not transfused after their first CVA had no recurrences, (median follow up = 7.9 years; 2–18 years), providing a basis for discussion on the indications of long-term transfusion therapy for sickle cell patients presenting with their first CVA.

Le dépistage néonatal de la drépanocytose en France métropolitaine

Le depistage neonatal d’une affection, qui engage lesfamilles dans des processus medicaux et psycholo-giques complexes, ne se justifie que si on peut enattendre un benefice superieur a son cout, en d’autrestermes si les mesures preventives mises en œuvrereduisent sa morbidite et sa mortalite. L’utilite desdepistages neonatals de la phenylcetonurie et del’hypothyroidie tient au fait aujourd’hui bien etabliqu’un regime ou un traitement hormonal substitutifprevient l’installation de degâts cerebraux severes.Les benefices apportes par la prise en charge de ladrepanocytose grâce a la mise en œuvre d’un depis-tage « cible » dans les populations « a risque » sontde nature differente. Son objectif est en effet dereduire la mortalite precoce liee aux infections aStreptococcus pneumoniae et aux sequestrationsspleniques. Il se justifie par la frequence de la mala-die drepanocytaire en France metropolitaine, surtoutdans les villes siege d’une immigration importante.Pour autant, la mise en œuvre du depistage neonatalde la drepanocytose n’est pas facile, et nous nousefforcerons d’analyser ici les principales difficultesrencontrees aujourd’hui.LA DREPANOCYTOSE EST FREQUENTEEN FRANCE METROPOLITAINELa drepanocytose a une frequence maximale en Afri-que subsaharienne, ou 20 a 30 % de la populationsont transmetteurs potentiels. La mutation est aussiretrouvee, certes a une frequence moindre, dans qua-siment tout le continent africain [1]. C’est la traitedes Noirs qui, jusqu’au siecle dernier, a amene letrait drepanocytaire aux Antilles, ou un habitant surhuit est heterozygote, et aux Etats-Unis. Ces dernie-res annees, ce sont les migrations de populations afri-caines a la recherche d’un travail qui ont concentrela maladie dans la plupart des grandes villes indus-trialisees d’Europe de l’Ouest. Mais la drepanocy-tose existe aussi dans le bassin mediterraneen, auProche-Orient, a Madagascar, en Inde... Ainsi, laFrance metropolitaine reunit des populations porteu-ses du trait drepanocytaire de differentes origines.Le recensement de 1990 chiffrait a quatre millionset demi le nombre de personnes originaires de pays arisque (Insee Premiere, juillet 1992, n° 217). Comptetenu d’une natalite plus elevee dans ces populations,on estime entre 75 000 et 150 000 par an le nombrede nouveau-nes a risque. En se referant aux obser-vations epidemiologiques de 1993 chez 600 enfantsdrepanocytaires, 69 % etaient d’origine africaine,28 % desAntilles et 3 % d’Afrique du Nord. Quatre-vingt pour cent de ces enfants atteints de syndrome

Traitement des patients drépanocytaires par hydroxyurée : efficacité et tolérance

Hydroxyurea is the unique drug having demonstrated an efficacy in preventing recurrences of painful crises, acute chest syndromes and in reducing transfusional needs in patients severely affected with sickle cell disease. However, there is a wide variation in the clinical response to hydroxyurea in sickle cell patients, with children generally experiencing greater benefits than adults. Short- and middle-term tolerances are good. Our uncertainties about long-term tolerance are mainly that we do not know the consequences of the drug on ulterior fertility in boys treated early and for long periods. Hydroxyurea has just been licensed for sickle cell adults and children in Europe. Its prescription for the moment must be restricted to severely affected patients, enrolled in long-term follow-up protocols.

Drépanocytose et atteinte vasculaire cérébrale chez l’enfant

In children with sickle-cell anemia, cerebral vasculopathy is a frequent and severe complication. It is attributed not only to erythrocyte sickling but also to multiple physiological modifications associated with sickle-cell anemia: platelet and leukocyte activation, endothelial injury and remodeling, coagulation activation, hemolysis and subsequent chronic inflammation, impaired vasomotricity, etc. Intracranial large-vessel remodeling leads to clinical cerebral infarction, whereas microvascular injury and impaired vasoreactivity lead to so-called silent infarcts, which are actually associated with impaired cognitive development. Primary prevention strategies have been developed to screen children for cerebral vasculopathy and to further reduce stroke risk. Annual transcranial Doppler beginning at 2 years of age is recommended, allowing risk stratification. Patients at high risk are enrolled in a monthly transfusion exchange program, which reduces the risk of a first stroke by 90 %. Chronic transfusion therapy has also demonstrated efficacy in preventing a second stroke, as a secondary prevention strategy. Lifelong treatment is recommended, as recurrent stroke has been observed when transfusion is discontinued. The burden of chronic transfusion is heavy for patients. Furthermore, several studies have shown that, despite preventing clinically symptomatic stroke, chronic transfusion therapy may not be effective concerning silent infarct progression. Other therapeutic options are currently being explored to obtain better protection with reduced side effects.