[Peripheral and bone marrow plasmacytosis in dengue fever: report of a case]. / Plasmocytose sanguine et médullaire au cours de la dengue : une observation.

We report a case of dengue fever with plasma cells in the blood (3980 per cubic millimeter) and bone marrow (30%) in a 55-year-old woman hospitalized for fever, arthralgias and thrombocytopenia (66,000 per cubic millimeter) on returning from the West Indies. Serological testing confirmed the diagnosis. Plasmacytosis is rare in dengue fever and its frequency and correlation with the different forms of the disease remain to be determined.

Management of haemophilic arthropathy.

Despite the tremendous benefit offered by primary prophylaxis, recurrent joint bleeding with progression to chronic synovitis and haemophilic arthropathy is still a daily concern for the multidisciplinary health care teams managing patients with severe haemophilia or haemophilia complicated by inhibitor development. Advanced stages of arthropathy could be prevented by regular assessment of musculoskeletal status and thus early detection of symptoms, daily rehabilitation exercises at home, and implementation of appropriate physiotherapy and medical training. Patient's education and psychological counselling are crucial. New tools such as magnetic resonance imaging are promising for the monitoring of these patients and might promote early detection of arthropathy and thus appropriate preventive measures to avoid further joint deterioration can be implemented. Medical synovectomy such as radionucleide synoviorthesis is a simple and non-invasive procedure that often delays the need for surgery which despite considerable improvement in techniques and postoperative rehabilitation remains a high-risk strategy in patients with severe haemophilia, especially those with inhibitors. In these high risk patients, availability of specific clotting factors such as activated prothrombin complex concentrate (FEIBA, Baxter, Vienna, Austria) and more recently, recombinant factor VIIa (rFVIIa, NovoSeven, Bagsvaerd, Denmark) has allowed to perform effective and safe orthopaedic procedures. The on-going EUREKA study will undoubtedly provide additional information about the optimal use of rFVIIa in this context.

Evidence for persistent hepatitis C virus (HCV) infection in hemophiliacs.

Hepatitis C virus (HCV) is the major etiologic agent associated with non-A, non-B hepatitis. This study was designed to assess virologic and serologic markers in hemophiliacs exposed to non-heat-treated and/or virus-inactivated plasma derivatives. Serial bleeds from 48 hemophilic patients were analyzed for the presence of HCV viral RNA sequences as detected by polymerase chain reaction (PCR) and antibodies to structural (core) and nonstructural (C-100 and 33C) proteins by specific dot immunoblot assay. All patients exposed to non-heat-treated products, and four of six patients exposed only to virus inactivated products, had evidence of HCV infection. However, over the 5-yr study period, six exposed patients (13%) consistently lacked detectable anti-C-100 and seven (15%) lost this antibody. HCV viremia (PCR positive) was found in 91% of exposed patients, and was significantly more frequent in HIV seropositive hemophiliacs (P less than 0.05). Six patients had high antibody level to HCV and elevated ALT, but appeared to clear viremia. Four hemophiliacs were HCV seropositive but lacked detectable viremia. These data indicate that hemophiliacs remain persistently infected by HCV and that antibody to the core antigen of HCV is a reliable marker of this transfusion transmissible agent.

Progression to AIDS in French haemophiliacs: association with HLA-B35.

OBJECTIVE: To evaluate whether HLA-B35 influences progression to AIDS in HIV-seropositive subjects with haemophilia. DESIGN: Retrospective (before 1985) and prospective (after 1985) follow-up of a group of French haemophiliacs. METHODS: We studied 144 seropositive patients with moderate or severe haemophilia A or B or von Willebrand's disease. Enzyme-linked immunosorbent assay was used to screen patient sera for total HIV antigen and core p24 antigen antibodies. All patients were typed for HLA A, B and C antigens in the same laboratory. Time of seroconversion was estimated to be the mid-point between the last seronegative test and the first seropositive test. AIDS-free survival curves were constructed using the Kaplan-Meier estimate and differences in survival analysed using the Mantel-Cox test. The Cox proportional hazards model was used to adjust for confounding variables. RESULTS: Median follow-up after seroconversion was 8.7 years (range, 3.5-10.7 years). By the end of the study, six HLA-B35-positive patients and 12 HLA-B35-negative patients had progressed to AIDS. Individuals with HLA-B35 showed a significantly faster rate of progression to AIDS over the follow-up period than HLA-B35-negative individuals (hazard ratio, 2.72; P = 0.037). After adjusting for type and severity of haemophilia, CD4 cell count at first seropositive test, age at seroconversion, and zidovudine treatment before AIDS, the hazard ratio was 2.74 (P = 0.045). CONCLUSION: HLA-B35 is a risk factor for more rapid progression to AIDS in subjects with haemophilia.

Haemophilia B due to a de novo insertion of a human-specific Alu subfamily member within the coding region of the factor IX gene.

A de novo insertion of an Alu repeated DNA element was found within exon V of the factor IX gene in a patient with severe haemophilia B. The element interrupts the reading frame of the mature factor IX at glutamic acid 96 resulting in a stop codon within the inserted sequence. The Alu repeat is 322 bp long, and the 5' region is shortened by 38 bp. The insertion created a target site duplication of 15 bp consistent with retroposition, and contains a pure polyadenine tract of at least 78 resides at the 3' end. The nucleotide sequence agrees with a consensus for an Alu subfamily which is evolutionarily the most recently inserted, suggesting that it is an exact copy of a putative source gene. These observations indicate that retroposition of Alu elements is a continual process and a mechanism for generating human genetic defects.

Assessment by gene amplification and serological markers of transmission of HIV-1 from hemophiliacs to their sexual partners and secondarily to their children.

The transmission of HIV-1 infection from men with hemophilia A to their female sex partners and secondarily to their children was studied by serological markers including antibody, antigen, and HIV genome as detected by the polymerase chain reaction (PCR). Among 27 sex partners of 26 seropositive hemophiliacs, 5 were seropositive-PCR positive (active), 11 were seronegative-PCR positive (latent), and 11 were negative for both. These results were confirmed by testing serial serum samples and paired samples of DNA from peripheral blood mononuclear cells (PBMCs) and serum from seronegative women. PCR negativity in exposed women was correlated with the use of condoms (p less than 0.01). Eight children from five couples were seronegative. However, HIV-1 infection as detected by PCR was transmitted to 60% of exposed children, including one from a seronegative-PCR positive mother.

Incidence of factor IX inhibitor development in severe haemophilia B patients treated with only one brand of high purity plasma derived factor IX concentrate.

Fifteen previously untreated patients (Pups) with severe haemophilia B (factor IX activity < or = 2 U/dl) only treated with one brand of plasma-derived high purity factor IX concentrate (FIX LFB) were studied. Age at first injection varied from 1 to 137 months and follow-up since this first injection from 21 to 86 months (median: 35). Cumulative exposure days (CED) were from 4 to over 100 (median: 26). Among these 15 Pups only one developed an inhibitor. Mutation analysis performed in all patients showed total gene deletion in the patient with inhibitor, partial gene deletion in another one, and missense mutations in 9 families. Mutation was not found in one patient. Actually, according to the data already published, only two patients were at high risk for inhibitor development in our population. Our study, although rather small, confirms the previously reported low incidence of inhibitors in haemophilia B. Large studies on incidence of FIX inhibitors are indeed difficult to perform, due to both the overall small number of severe haemophilia B patients and the low incidence of FIX inhibitors. Consequently, the impact of bias, such as prevalence of different types of gene defects in a given population, is major. Therefore, any study, dealing with incidence of FIX inhibitors in severe haemophilia B should report, for each patient, the type of gene defect.

Incidence of factor VIII inhibitor development in severe hemophilia A patients treated only with one brand of highly purified plasma-derived concentrate.

The incidence of factor VIII inhibitor was studied in a cohort of 56 previously untreated patients with severe hemophilia A (factor VIII below 1 U/dl). They received only one brand of highly purified factor VIII concentrate (HPSD-VIII) prepared by conventional chromatography with a solvent-detergent step for viral inactivation. Follow-up since the first infusion of HPSD-VIII was from 1 to 76 months (mean = 29) and cumulative exposure days (CED) from 1 to over 100 (median = 26). Five patients (9%) developed an inhibitor after 6 to 19 CED, only one being a high responder (2%), showing a low incidence of inhibitor compared with previous studies using high purity plasma-derived or recombinant products.

Use of recombinant factor VIIa in 3 patients with inherited type I Glanzmann's thrombasthenia undergoing invasive procedures.

The treatment of bleeds in Glanzmann's thrombasthenia is a challenging issue, especially when repeated platelet transfusions have induced anti-glycoprotein (GP) IIb-IIIa or anti-HLA allo-immunisation. In an attempt to find an alternative treatment regimen, we used recombinant factor VIIa (rFVIIa, NovoSeven, Novo Nordisk, Denmark) as first-line therapy in 3 patients with Glanzmann's thrombasthenia and anti-GPIIb-IIIa iso-antibodies who were scheduled for invasive procedures. The administration of an initial bolus dose of rFVIIa (70-110 microg/kg) was immediately followed by continuous infusion at the rate of 9-30 microg/kg/h for 3-15 days. The treatment resulted in an excellent clinical efficacy and tolerance in 2 cases. In the third patient, whereas efficacy was excellent at the surgical site, pharyngonasal bleeds of traumatic origin persisted for 10 days, and a severe thromboembolic complication occurred 5 days after discontinuation of rFVIIa. Complementary studies are needed for patients with congenital platelet disorders in order to evaluate the safety and the potential therapeutic place of rFVIIa treatment.

French previously untreated patients with severe hemophilia A after exposure to recombinant factor VIII : incidence of inhibitor and evaluation of immune tolerance.

Fifty French previously untreated patients with severe hemophilia A (factor VIII < 1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (> or = 10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.

Predictive value of viral load and other markers for progression to clinical AIDS after CD4+ cell count falls below 200/microL. SEROCO & HEMOCO Study Group.

BACKGROUND: To assess the predictive value of biological and clinical events for progression to AIDS (1993 European classification) when the CD4+ cell count falls below 200/microL (CD4 threshold) in different exposure groups. To investigate whether such markers remain predictive independently of the serum HIV-1 RNA level at the CD4 threshold. METHODS: The predictive value of biological and clinical events occurring during the 24 months prior to the occurrence of CD4 threshold (n = 333) was quantified in a Cox model. Another Cox model was carried out in a subset of 77 patients in whom viral load from stored sera was available. Furthermore, changes in viral load during the 24 months preceding the CD4 threshold were assessed in a mixed model according to subsequent development of AIDS. RESULTS: Among the 333 patients, the slope of the CD4+ cell counts, the emergence of p24 antigen, persistent thrush, and age at the CD4 threshold were independent predictors of progression to clinical AIDS (44.7%). Among the subset of 77 patients, the HIV-1 RNA level at the CD4 threshold, persistent thrush and age remained independent predictors of progression to AIDS (45.5%). The increase of the HIV-1 RNA level was moderate, both in non-progressors (24.0% per year) and in those who subsequently developed AIDS (27.1% per year), (P = 0.93). Viral load was consistently higher in the latter group (P = 0.002). CONCLUSION: At a late stage of infection, age and persistent thrush remain predictive of progression to AIDS, independently of viral load.

Synovectomy of the elbow in young hemophilic patients.

Synovectomy of twenty-three elbows was done in eighteen patients, eight to twenty-five years old, who had severe hemophilia and were followed for eighteen to seventy months. Episodes of bleeding recurred in four elbows, and moderate pain persisted in three. A significant improvement in mobility was observed for pronation-supination in nine elbows and for flexion-extension in fourteen. No radiographic evidence of arthritis was seen. Synovectomy of the elbow, performed through a single lateral incision, appears to be a valuable surgical procedure in hemophiliacs in whom non-operative treatment has failed, and resection of the radial head should be done in adults when there is moderate or severe damage to the cartilage of the radial head.

Carrier detection and prenatal diagnosis in 98 families of haemophilia A by linkage analysis and direct detection of mutations.

489 individuals from 98 families with a haemophilia A member were studied with restriction fragment length polymorphisms (RFLPs) for carrier detection and prenatal diagnosis. Five intragenic polymorphisms revealed with the restriction enzymes BclI, XbaI, BglI, HindIII and AlwNI and one extragenic multiallelic polymorphism (St14) at the DXS52 locus were used. The combination of the five intragenic polymorphisms did not add significantly more information than just the BclI and XbaI polymorphisms because of strong linkage disequilibrium. The sequences surrounding the intronic restriction sites of the BclI and XbaI RFLPs are known so they can be rapidly analysed using the polymerase chain reaction (PCR). 68.6% of the women were heterozygous for either the BclI or XbaI RFLP and this heterozygosity rate increased to 98.6% when the St14 extragenic polymorphism was included. Linkage analysis using these RFLPs led to the classification of over 90% of the women as carriers or normal and 98.6% of the carriers were heterozygous. Prenatal diagnosis was successful in the 16 foetuses tested and all could be classified as carrier, normal or haemophiliac. Five TaqI restriction sites in the coding region of the factor VIII gene can detect a C to T transition that results in an in-frame stop codon. These five sites were amplified by PCR in 119 haemophiliacs and tested for an abnormal TaqI restriction pattern. A stop codon was found in three haemophiliacs at exons 18, 22 and 24. The same analysis revealed three deletions, two involving the last exon 26 and one exons 23-26.

[Parvovirus B19 and pediatric pathology]. / Parvovirus B 19 et pathologie pédiatrique.

B 19 parvovirus is a widespread virus with primary infestation generally occurring in childhood through family and community outbreaks. Its most typical manifestation is transient erythroblastopenia with aplastic crisis, often profound, mostly affecting patients with chronic hemolytic anemia, and eventually patients with defective erythropoiesis (chronic hypoplastic anemia, iron deficiency anemia). In normal individuals the primary infestation is usually asymptomatic but may give transient hematological signs for few days: moderate reticulocytopenia, thrombopenia and neutropenia. Clinically two phases of the infection are described: 1.) a first phase of viremia of 2 to 3 days which may be accompanied by fever and myalgias; 2.) a second phase which may last for several weeks with dermatological signs, the most typical being erythema infectiosum, vasculitis, arthralgias or arthritis. In pregnant women, the primary infestation with B 19 parvovirus may lead to fetal anemia and hydrops fetalis with uneven outcomes: fetal death, chronic erythroblastopenia after birth, spontaneous resolution. Although the incidence of fetal infestation in non immunized pregnant women is still unknown, the question is raised of the recognition and protection of non immunized pregnant women at high risk of exposition to infested subjects. Long term persistence of the virus in the organism may be responsible for chronic manifestation, essentially but not exclusively in immunodeficient-patients: prolonged erythroblastopenia and chronic rheumatologic manifestations. It may be also responsible for cases of juvenile arthritis, thrombocytopenic purpura and chronic neutropenia of childhood. The diagnosis of the viral infestation is mainly based upon the detection of specific IgM, then IgG, antibodies by Elisa technique.

[Autoimmune thrombopenia and pregnancy. Value of counting scalp platelets]. / Thrombopénie auto-immune et grossesse. Intérêt de la numération de plaquettes au scalp.

Fetuses of mothers who have auto-immune thrombocytopenia are at risk in utero of having transitory thrombocytopenia. There is no maternal biological test that can predict the numbers of platelets in the fetus. This count of platelet numbers can be estimated from taking fetal blood from the scalp at the onset of labour, and if the count is less than 50 X 10(9) per litre a caesarean operation is indicated. The authors report a series of 23 pregnancies where the mother had auto-immune thrombocytopenia and where fetal scalp blood sampling was indicated. This series has been compared with a previous series of 14 pregnancies where scalp sampling was not carried out. There was no case of severe fetal thrombocytopenia after scalp sampling was carried out and where the best way of delivery could be predicted early enough in each case. The ease of taking the sample and the safety and reliability of it for estimating the degree of thrombocytopenia in the fetus and thus deciding the method of delivery makes us believe that this method should be used more frequently in cases of maternal thrombocytopenia that appear late in pregnancy.

[Acquired autoantibodies directed against human factor VIIIc. Treatment of 2 hemorrhagic accidents with porcine factor VIIIc]. / Auto-anticorps acquis contre le facteur VIIIc humain. Traitement de deux accidents hémorragiques par le facteur VIIIc porcin.

The emergence of an autoantibody directed against factor VIII may be responsible for severe, life-threatening haemorrhages. This rare disease is usually idiopathic, but it may be consecutive to an autoimmune disease or to the absorption of certain drugs such as penicillin. The diagnosis rests on the finding of a prolonged activated thromboplastin time with presence of a circulating anticoagulant and deep fall in factor VIII level. Two cases of severe haemorrhage successfully treated with porcine factor VIIIc are reported. The first case concerned an 80-year old woman presenting with a large haematoma of the thigh uncontrolled by injections of human factor VIIIc. The second case was that of a 24-year old woman in a state of shock due to a pleural blood effusion that occurred during heparin treatment of cerebral thrombophlebitis, combined with penicillin treatment of bronchial superinfection. In both cases the high-titer autoantibody to the human factor VIIIc did not, or little, cross with porcine factor VIIIc. Factor VIII rose after the first injection of the porcine factor, and the haemorrhage was rapidly controlled. In both cases, the autoantibody disappeared within a few months, either spontaneously or after treatment with immunosuppressants.

[Efficacy in viral inactivation of the concentrates of factor VIII and IX by the solvent/detergent procedure. Evaluation in patients with hemophilia]. / Efficacité de l'inactivation virale des concentrés de facteur VIII et IX par procédé solvant-détergent. Evaluation chez l'hémophile.

Human immunodeficiency virus (HIV) infection and hepatitis virus B or C (HBV, HCV) transmission are major risks following infusion of coagulation factor concentrates. Thus, several methods have been used to achieve viral inactivation of concentrates prepared from plasma collected from a large number of donors. In this study, 32 patients with haemophilia A or B (n = 31) or von Willebrand's disease (n = 1) were treated between 1987 and 1990 only with factor VIII or IX concentrates inactivated by the solvent-detergent procedure. During this period, none of these cases exhibited elevated liver enzymes (alanine amino transferase), and serological tests for HIV, HBV and HCV infections always remained negative. This suggests that the solvent-detergent procedure of concentrate inactivation is an efficient method to prevent not only HIV or HBV transmission but also HCV infection in haemophiliacs.

[Which urologic treatment alternatives are there for the hemophiliac patient?]. / Quels traitements urologiques sont possibles chez un hémophile?

OBJECTIVE: Urological procedures are hazardous for hemophilic patients. The aim of this work is to report the treatment of 22 hemophilic patients in order to define prognosis factors and treatment options. MATERIAL AND METHODS: 22 patients have been treated: 8 had severe hemophilia, 5 A (FVIII < 1%), 3 B (F IX < 1%), 2 had moderate hemophilia A (FVIII 2 to 6%) and 10 minor hemophilia A (F VIII 7 to 30%). Two had acquired hemophilia with auto-anti-FVIII antibodies (ab). Four patients were HIV+. Eighteen patients were first referred to our hospital, and 3 were transferred from an other institution for persistent hematuria: one with anuria, one after bladder neck incision, and the other following suprapubic prostatectomy. RESULTS: For patients without FVIII ab, a sufficient level of FVIII or IX (> 60%), could be achieved pre-operatively and maintained post operatively (4 to 20 days, according to the surgical procedure) by injections of FVIII, FIX or by injections of desmopressin. For one haemophilia A patient with anti-F VIII ab, transferred for uncontrollable bleeding after bladder neck incision, selective arterial embolization was successful. But for 2 patients with acquired haemophilia, improvement of the coagulation was insufficient, with human or porcine FVIII, activated prothombic complex concentrates or recombinant activated FVII. In spite of surgical procedures and arterial embolizations the 2 patients died. CONCLUSION: The urological treatment of haemophilic patients needs to be performed in specialised centers. For patients without FVIII ab, classical urological procedures can be performed. But for patients with FVIII ab when alternative treatments (radiotherapy, LHRH agonists) can be used, the surgical procedures must be delayed; in emergency if hemostasis cannot be achieved arterial embolization could be useful.

[Management of hemophilia]. / Prise en charge de l'hémophile.

Progress for the care of severe haemophilia patients were major in the last 20 years (Factor VIII and IX concentrates, on demand home treatment, prophylactic treatment, comprehensive haemophilia centers) allowing a quite normal life up to the contamination by HIV of 50 p. 100 of french haemophiliacs.