Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability.

Essentials Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism. Children aged 1 to < 12 years were given dabigatran etexilate in an open-label, single-arm study. The pharmacokinetic-pharmacodynamic relationship was similar to that seen in adult patients. There were no serious adverse events, bleeding events or recurrent venous thromboembolism. SUMMARY: Background The current standard-of-care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option. Objectives To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE. Patients/Methods Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age-adjusted and weight-adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics-related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)-pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs). Results Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady-state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non-linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single-dose group (screening period) and in one patient in the multiple-dose group (on-treatment period). Conclusion The current study supports the further evaluation of DE OLFs in pediatric patients with VTE.

Haemophilia patients' unmet needs and their expectations of the new extended half-life factor concentrates.

INTRODUCTION: National Member Organisations (NMO) of persons with haemophilia (PWH) from the DACH Region (D = Germany, A = Austria, CH = Switzerland) were interested to better understand PWH's expectations and concerns of extended half-life (EHL) factor concentrates (FC) before availability in these countries. METHODS: Based on an expert meeting and focus groups conducted across Germany a survey for haemophilia patients and their parents was developed and was sent out to 2,644 PWH. RESULTS: One thousand and seven questionnaires were sent back (38.1%); 743 adults and 262 parents. Most patients had haemophilia A (84.5%), were severely affected (73.7%), received prophylaxis (57%) and used recombinant FC (60.2%). One-quarter did not know the correct half-life of their FC [HA/FVIII: 26%, HB/FIX: 31.1%]. Four percent were unsatisfied with their current FC, mainly with short half-life of FC and difficult manageability. They expected from new EHL products less frequent injections (55.2%), better efficacy (32.1%) and safety/no side effects (15.7%); 59.5% would be willing to switch to new products if they have a prolonged half-life and the same safety of the current FC. They wish more information about half-life (84.4%), possible side-effects (81.3%) and efficacy (77%) and wanted to receive information about new products from their haemophilia treater (76.3%) and the newsletter of their NMO (74.3%). Significant differences across countries were found. CONCLUSIONS: The representative survey could show that although PWH were generally satisfied with their current FC, the majority would be willing to switch to EHL products assuming half-life is prolonged and has the same safety of the current FC.

Incidence and predictors of indwelling arterial catheter-related thrombosis in children.

BACKGROUND: Indwelling arterial catheters (IACs) are used for monitoring and blood sampling purposes in intensive care units. Very limited information is available on the incidence and risk factors of IAC-related thrombosis in children. OBJECTIVE: To investigate the incidence and predictors of IAC-related thrombosis in a tertiary care pediatric hospital. METHODS: For a period of 12 months, detailed information was prospectively recorded for all consecutive children requiring IACs. RESULTS: Six hundred and fifteen IACs were placed in a total of 473 children at a median age of 0.56 years for a total of 47440.84 catheter hours. Of the 615 IACs, 418 (68%) were placed in the radial artery, 137 (22%) in the femoral artery, 26 (4%) in the umbilical artery, 11 (2%) in the brachial artery, and 23 (3.7%) in another artery. Thrombosis occurred in 20 cases, reflecting an overall incidence of 3.25%. Eighteen of the 20 IAC-related thrombi were located in the femoral arteries, reflecting a relative incidence of 13% (18/137). Newborn age, lower body weight, low cardiac output and increased hematocrit were significantly related with an increased risk of femoral artery thrombosis. In logistic regression analysis, younger age (P<0.001, odds ratio 6.51) was independently associated with an increased thrombotic risk. CONCLUSIONS: This study demonstrates that arterial thrombosis occurs with an increased incidence in children requiring IACs in the femoral location. Younger age is independently associated with an increased risk of thrombosis. The radial location is safe, and should be preferred to the femoral location.

Intrauterine subdural hemorrhage in a preterm neonate possibly associated with maternal low-molecular weight heparin treatment.

We report intrauterine subdural hemorrhage in a preterm infant delivered by cesarean section at 32 weeks following vaginal bleeding of a mother treated with low-molecular weight heparin (LMWH) for deep vein thrombosis. The subdural hematomas were partially calcified, proving antenatal occurrence. Maternal trauma during pregnancy, intrauterine infection, cerebral vascular malformation and congenital coagulopathy as known etiologies of subdural hemorrhage could be ruled out. Intrauterine subdural hemorrhage may be an exceptional complication of maternal LMWH treatment.

Severe bleeding complications during antiepileptic treatment with valproic acid in children.

Valproic acid (VPA) is an antiepileptic drug frequently used in children. Although VPA can cause a variety of laboratory abnormalities affecting haemostasis, controversy exists about the clinical relevance of such haematological abnormalities. We report on 4 children with severe bleeding complications while on VPA therapy; two presented with intracranial bleeding, while two suffered from severe bleeding postoperatively. Diagnostic and therapeutic measures are discussed that help to avoid severe bleeding complications in children with VPA treatment.

Disseminated Fusarium oxysporum infection in hemophagocytic lymphohistiocytosis.

The portal of entry of disseminated Fusarium spp. infections is still not clearly defined. We report on a disseminated Fusarium oxysporum infection occurring during a long period of severe neutropenia in a child with hemophagocytic lymphohistiocytosis. A nasogastric feeding tube was the possible source of entry of the fungus.

Hepatic steatosis: a frequent non-specific finding in HIV-infected children.

Thirty HIV-infected children were cross-sectionally examined for morphologic hepatic abnormalities, using ultrasonography or histology. Abdominal ultrasonography was performed in 27 children. The liver structure was normal in four patients, one of whom had moderate symptoms of the HIV infection and three of them severe symptoms. Abnormal liver structure, compatible with hepatic steatosis, was found in 23 (85%) patients. Five of them were in an early stage of the HIV infection (category N or A), three patients were ranked in category B and 15 patients in category C. Histological examination of the liver was performed in 11 children and steatosis was documented in ten (91%). In seven (70%) of these ten children steatosis had been suspected by ultrasonography. In conclusion, steatosis is common in HIV-infected children. It is non-specific and has no impact on disease, diagnostic evaluation or management. Conclusion Ultrasonography is a sensitive, accurate, non-invasive screening tool. It is more reliable than liver function tests.

Sporadic tuberculous meningoencephalitis.

Tuberculous meningoencephalitis in a 24-month-old boy is reported. He contracted the infection from his apparently healthy grandfather with unnoticed pulmonary tuberculosis, as suggested by restriction fragment length polymorphism analysis of the isolated pathogen.

Diagnostic value of cerebrospinal fluid examination in children with peripheral facial palsy and suspected Lyme borreliosis.

Our objective was to determine the diagnostic value of CSF examinations in the diagnosis of neuroborreliosis in children with peripheral facial palsy (PFP). Paired serum and CSF samples from 21 children with PFP were investigated for antibody responses to Borrelia burgdorferi antigens using three different ELISA systems and one Western blot assay. Twenty of the children (95%) had detectable immunoglobin (Ig) M or IgG in the acute-phase serum, but discrepancies between serologic assays were noted in 33% for IgM and 22 to 50% for IgG. Intrathecal specific-antibody production was detected in five of the 20 seropositive children (25%). These five patients showed seroconversion in convalescent sera in at least one assay. Similar seroconversion suggesting recent infection with B. burgdorferi was observed in eight of the 10 children (80%) without intrathecal specific-antibody production, from whom convalescent serum samples could be obtained. All patients with intrathecal antibodies or seroconversion had shown lymphocytic pleocytosis in the acute phase of PFP. In the acute phase of PFP the detection of intrathecal production of antibodies to B. burgdorferi allows prompt diagnosis of neuroborreliosis. For patients with lymphocytic pleocytosis but no detectable intrathecal antibodies, analysis of convalescent serum may help to establish this diagnosis.

Cerebral tuberculosis presenting as complex febrile convulsions.

Complex febrile convulsions were the initial clinical manifestation of miliary tuberculosis in a 4-year-old immigrant girl. The cerebral lesions were visible only after contrast-enhanced cranial computed tomography (CT) while native CT scan as well as cell count and glucose concentration in the cerebrospinal fluid were normal. Mycobacterium tuberculosis was cultured from gastric aspirate and liver biopsy tissue. Treatment with isoniazid and rifampin for 12 months, pyrazinamide for 9 months, and ethambutol for the initial 6 weeks resulted in resolution of the cerebral lesions but a retinal scar after granuloma formation in the right eye caused reduced visus. This case demonstrates the importance of thorough search for tuberculosis even in the absence of overt clinical pulmonary signs especially in high-risk individuals such as immigrants.

T-cell death by apoptosis in vertically human immunodeficiency virus-infected children coincides with expansion of CD8+/interleukin-2 receptor-/HLA-DR+ T cells: sign of a possible role for herpes viruses as cofactors?

One mechanism proposed to play a role in T-cell depletion in human immunodeficiency virus (HIV) infection is apoptosis (activation-induced cell death). We assessed whether apoptosis is related to activation of T cells in vivo and its possible triggers. DNA was extracted from peripheral blood mononuclear cells (PBMC) taken from 16 vertically HIV-infected children and 9 HIV-negative children born to HIV-positive mothers (controls) and tested by agarose gel electrophoresis for the presence of DNA fragments specific for apoptosis. Signs of apoptosis were found on in vitro culture of PBMC from 12 of 16 HIV-infected children, but not in PBMC from the nine controls. Eleven of the 12 HIV-infected children with apoptosis showed an elevated (> 15%) proportion of CD3+/HLA-DR+ cells. This was due to an increased proportion of CD8+/HLA-DR+ cells, as shown in 7 of 7 further tested patients. In none of the probands an increased (> 5%) proportion of IL-2 receptor expressing CD3+ cells was found. T cells undergoing apoptosis were preferentially of the CD8+ phenotype. Expansion of circulating CD8+/interleukin-2 receptor (IL-2R)-/HLA-DR+ T cells is known to occur during active infection with herpes viruses. To investigate the possible role of herpes viral coinfections for apoptosis in HIV infection, we focused on Epstein-Barr virus (EBV) as an example for a herpes virus usually acquired during childhood. In 10 of 12 patients with apoptosis, we found increased levels of EBV genome in PBMC and/or tissues, indicating active EBV replication. By contrast, no increased burden of EBV was found in the four HIV-infected patients without apoptosis or in the controls. Our data indicate that in children the occurrence of apoptosis in HIV infection is closely related to activation of CD8+ T cells. Furthermore, primoinfection with or reactivation of herpes viruses, such as EBV, may substantially contribute to such T-cell activation and the ensuing apoptosis. Additional studies are warranted to evaluate the contribution of herpes virus-triggered apoptosis to the T-cell loss leading to the acquired immunodeficiency syndrome.

[Pneumocystis carinii pneumonia in infants with vertically acquired HIV infection in Switzerland]. / Pneumocystis-carinii-Pneumonie bei Säuglingen mit vertikaler HIV-Infektion in der Schweiz.

OBJECTIVE: Review of incidence, clinical picture, therapy, and outcome of Pneumocystis carinii pneumonia (PCP) in infants with vertically-acquired HIV infection in Switzerland. METHODS: Inquiry among members of the Swiss Pediatrics AIDS Group, review of the data base of the Swiss Neonatal HIV Study and retrospective analysis of the charts from infants with PCP. RESULTS: Since 1986 PCP has been diagnosed in 10 out of 107 infants with vertically-acquired HIV infection. PCP occurred in 7 infants at the age of 3-6 months and in 3 at the age of 9-11 months. 4 infants showed symptoms related to HIV infection before developing PCP. Before the development of PCP, infection with HIV had been ascertained in 6 infants. In 2 the diagnosis was still unclear and in the 2 remaining the risk of HIV infection was not known. None of the infants was on primary prophylaxis against PCP. Signs and symptoms of PCP included cough and tachypnea (100%) as well as high fever up to 40 degrees C (90%). Transcutaneous oxygen saturation was 70-95%. Chest X-rays revealed interstitial infiltrates in 6 infants, localized infiltrates in 2 and interstitial as well as localized infiltrates in 2. The CD4+ cell count was, with one exception, < 1500/microliters, i.e. below the normal value for age. Side effects of high dose cotrimoxazole were noted in 6 patients. 5 infants required intubation and mechanical ventilation. 4 infants died due to PCP, including 3 of those who required intubation and mechanical ventilation. CONCLUSIONS: PCP in infants with vertically-acquired HIV infection preferentially occurs at the age of 3 to 6 months and is often lethal, especially in patients requiring intubation. Evaluation for HIV infection should be done as early as possible in order to introduce primary PCP prophylaxis in infants at risk for this opportunistic infection.