Oliver Andres

Indoleamine 2,3-dioxygenase mediates cell type-specific anti-measles virus activity of gamma interferon.

ABSTRACT Gamma interferon (IFN-γ) has been shown to be increased in sera from patients with acute measles and after vaccination, to exhibit protective functions in brains of patients with subacute sclerosing panencephalitis, and to mediate a noncytolytic clearance of measles virus (MV) from rodent brains. In order to reveal a possible intracellular antiviral activity in the absence of antigen presentation and cytotoxic T cells, we investigated IFN-γ-induced effects on MV replication in various tissue culture cells. While attenuated MV strains are more sensitive to IFN-α/β than are wild-type strains, IFN-γ inhibits the replication of all MV strains in epithelial, endothelial, and astroglial cells, but not in lymphoid and neuronal cell lines. The antiviral activity induced by IFN-γ correlates with the induction of indoleamine 2,3-dioxygenase (IDO), an enzyme of the tryptophan degradation pathway known to mediate antiviral as well as antibacterial and antiparasitic effects. The IFN-γ-induced antiviral activity can be overcome by the addition of excess amounts of l-tryptophan, which indicates a specific role of IDO in the anti-MV activity. Our data suggest that the IFN-γ-induced enzyme IDO plays an important antiviral role in MV infections of epithelial, endothelial, and astroglial cells.

Platelets in neonates: Central mediators in haemostasis, antimicrobial defence and inflammation

Platelets are not only centrally involved in haemostasis, but also in antimicrobial defence and inflammation. Since evaluation of platelet physiology in the particular patient group of preterm and term neonatal infants is highly restricted for ethical reasons, there are hardly any data available in healthy and much less in extremely immature or ill neonates. By summarising current knowledge and addressing both platelet researchers and neonatologists, we describe neonatal platelet count and morphology, report on previous analyses of neonatal platelet function in primary haemostasis and provide insights into recent advances in platelet immunology that considerably impacts our clinical view on the critically ill neonatal infant. We conclude that neonatal platelets, originating from liver megakaryocytes, substantially differ from adult platelets and may play a pivotal role in the pathophysiology of neonatal sepsis or intraventricular haemorrhage, both complications which seriously augment perinatal morbidity and mortality.

Even in pneumococcal sepsis CD62L shedding on granulocytes proves to be a reliable functional test for the diagnosis of interleukin-1 receptor-associated kinase-4 deficiency.

A 9-month-old infant presented with fatal pneumococcal sepsis and attenuated inflammation indices. Even in septic conditions, flow cytometry–based CD62L shedding test on granulocytes proved to be a fast and reliable diagnostic tool for the detection of a defect in the innate immunity. Confirmatory immunologic and genetic assays identified an autosomal-recessive interleukin-1 receptor–associated kinase-4 deficiency due to compound heterozygous mutations.

A novel two‐nucleotide deletion in HPS6 affects mepacrine uptake and platelet dense granule secretion in a family with Hermansky–Pudlak syndrome

Hermansky–Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by oculocutaneous albinism and platelet dysfunction. We report on a novel HPS6 homozygous frameshift variant (c.1919_1920delTC; p.Val640Glyfs*29) in a nonconsanguineous Caucasian family with two affected siblings (index patients) who presented with oculocutaneous albinism at birth and a mild bleeding phenotype during childhood and adolescence.

Fulminant skin GvHD with a cytokine pattern resemblant of cytokine release syndrome successfully treated with multimodal immunosuppression including tocilizumab

Acute Graft‐versus‐Host‐Disease (GvHD) is a potentially life‐threatening complication after allogeneic stem cell transplantation. If not treated early and adequately, the complex immunological mechanisms may lead to a self‐perpetuating cycle of alloreactivity, which is then associated with a high mortality. Here we assessed the cytokine profile on a daily basis in a patient with grade 4 skin GvHD, demonstrating a signature resembling cytokine‐release‐syndrome. After multimodal immunosuppressive intervention, including treatment with the IL6 receptor‐blocking antibody tocilizumab, the severe clinical symptoms unexpectedly resolved within 48hr. Pediatr Blood Cancer

Hyperfibrinolysis and acquired factor XIII deficiency in newly diagnosed pediatric malignancies

Bleeding events in patients with leukemia or malignant tumors can seriously complicate diagnostic interventions or therapeutic procedures, and may increase cancer-associated morbidity and mortality. Bleeding signs due to thrombocytopenia are frequent, especially in patients with malignant

Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37

Gene expression during hematopoietic lineage commitment is tightly regulated by a complex network of transcriptional regulators. Growth Factor Independent 1 (GFI1) and GFI1B are recruiters of histone deacetylases, histone methyltransferases, and key transcriptional repressors during hematopoiesis.[1

Diagnosis of platelet function disorders: A standardized, rational, and modular flow cytometric approach

Abstract A high proportion of patients with mucocutaneous bleeding diathesis and suspected inherited or acquired platelet disorder remain without diagnosis even after comprehensive laboratory testing. Since flow cytometry allows investigation of resting and activated platelets on the single cell level by requiring only minimal amounts of blood, this method has become an important assay within the diagnostic algorithm, especially in pediatrics. We therefore developed a standardized and modular flow cytometric approach that contributes to clarify impaired platelet function in a rational step-by-step manner. Due to simultaneous analysis of four fluorophores in a basic panel design, we are able to readily detect the most common and clinically significant platelet disorders: Glanzmann thrombasthenia or Glanzmann-like diseases (fibrinogen receptor GPIIb-IIIa), Bernard–Soulier syndrome (von Willebrand-factor receptor complex GPIb-IX-V) and less well characterized β1-integrins that serve as the collagen, laminin or fibronectin receptor (CD29-CD49b, e and f, respectively). Platelet reactivity was investigated in response to the agonists adenosine diphosphate (ADP) and thrombin receptor activator peptide 6 (TRAP6) in suboptimal and optimal concentrations by quantifying surface expression of activation markers CD62P and CD63 as well as binding of PAC-1 antibody to the high affinity conformation of the fibrinogen receptor. For advanced diagnostic questions, several further modules were implemented: (i) calcium mobilization for evaluation of early signal transduction, (ii) a kinetically resolved mepacrine assay for estimation of delta-granule content and release, and (iii) a module to determine platelet reactivity upon additional agonists like the thromboxane A2-analogue U46619 or collagen. Blood withdrawn from a healthy control cohort allowed generating preliminary standard values for all parameters. The modules were validated by analysis of patients with known or suspected platelet defects (leukocyte-adhesion deficiency type III, Wiskott–Aldrich syndrome, acute myeloid leukemia, sickle cell disease and chronic immune thrombocytopenia).

Early postnatal diagnosis of hereditary spherocytosis by combining light microscopy, acidified glycerol lysis test and eosin-5′-maleimide binding assay

Exact diagnosis of hereditary spherocytosis (HS) is widely considered unreliable around birth. However, early postnatal diagnosis at the beginning of congenital hemolysis may be essential for managing neonatal anemia and hemolytic icterus, identifying those at high risk for severe hyperbilirubinemia, irreversible kernicterus, or sudden need for red cell transfusion. We analyzed 37 blood samples from neonates or infants up to six weeks of life that had been collected in-house or shipped to our laboratory due to suspected red cell membrane disorder. By combining assessment of red cell morphology, acidified glycerol lysis test (AGLT), and eosin-5′-maleimide (EMA) binding assay, we were able to clearly exclude HS in 22 and confirm HS in 10 patients, of which one had undergone red cell transfusion prior to blood sampling. Assessment of red cell morphology and normal test results allowed diagnosis of infantile pyknocytosis or Heinz body anemia in three neonates. Re-evaluation of five patients with inconsistent results of AGLT and EMA binding led to confirmation of HS in two cases. Automated analysis of hematologic parameters revealed elevated proportion of hyperdense cells to be a highly significant indicator for HS in neonatal infants. We showed that assessment of red cell morphology in combination with AGLT and EMA binding assay is a reliable basis for confirming or rejecting suspected diagnosis of HS even in neonates. Our data underline the necessity for blood sampling and laboratory exploration in suspected red cell membrane or enzyme defects at the earliest occasion.

Haemophilia in extreme immature preterm infants: increased risk for intracranial haemorrhage?

Abstract Haemophiliacs and extremely premature infants are both at an increased risk for intracranial haemorrhage; both conditions might be further elevating the risk. We report a case of a very immature preterm-infant of 26 gestational weeks (birth weight 635 g) with severe haemophilia A. Furthermore, we provide an overview of the published literature on this subject matter. Until now, deficiency of factor VIII or IX as a potential risk factor for ICH in preterm infants remains controversial. However, prophylactic substitution of factor VIII or IX in preterm infants with haemophilia may minimize the risk of bleeding complications and neurologic sequelae.