Epidemiology and clinical characteristics of pandemic (H1N1) 2009 influenza infection in pediatric hemato-oncology and hematopoietic stem cell transplantation patients.

BACKGROUND: For children with hemato-oncologic diseases, especially after hematopoietic stem cell transplantation (HSCT), the risk for developing complications related to pandemic influenza A (H1N1) 2009 (pH1N1) infection is largely unknown. METHODS: A retrospective chart study was performed of pH1N1 cases diagnosed between October 2009 to January 2010 in the hemato-oncologic unit of the University Children's Hospital of Düsseldorf, Germany. FINDINGS: In total, 21 children were diagnosed with laboratory-confirmed pH1N1; in 16 patients with malignancies (acute leukemia 7, lymphoma 4, solid tumors 2, others 3) and in 5 with benign hematologic disorders. Five patients had undergone prior HSCT, although 1 patient was diagnosed during conditioning therapy with high-dose chemotherapy in preparation for haploidentical HSCT. Most frequent symptoms were fever (>38.5°C) and cough (in 100%), and rhinorrhea (57%). The 2 patients acquiring pH1N1 infection under high-dose or intensive chemotherapy did not require intensive care or mechanical ventilation, and both recovered under antiviral therapy. Oseltamivir was administered to 11 patients; in 1 patient, therapy was switched, on a compassionate-use basis, to intravenous zanamivir because of lack of clinical improvement after oseltamivir therapy. Complications were hospitalization (19%), demand of oxygen supplementation, delay/interruption of antineoplastic therapy, and prolonged administration of antibiotics and antipyretics. CONCLUSION: In the investigated patient population, pH1N1 was mild in most cases, but was associated with substantial morbidity in a proportion of patients and led to interruption and delay in anticancer treatment.

Invasive aspergillosis in pediatric oncology patients: a rare event with poor prognosis--case analysis to plan better targeted prophylactic or therapeutic measurement.

Despite the implementation of new antifungal drugs, invasive aspergillosis (IA) still remains a considerable challenge in pediatric oncology with a severe mortality. Prophylactic and therapeutic measurement have to be evaluated in these rare but poor prognostic patients. Therefore the entire group of patients at risk of developing IA has to be defined before cooperative prospective trials. In a retrospective analysis including all our patients with malignancies we looked for patients with proven/probable IA. Cases of the period from 2003 to 2008 were analyzed in detail.In the period between 2003 to 2008 24 of 755 patients were affected by proven/ probable IA. Compared to former studies incidence increased from 1.3%in 1980 to 3.4% in 2008. AML patients with or without allogeneic/haploidentical stem cell transplantation were at highest risk (24% and 25% respectively, in comparison to 1% in ALL-patients). Survival after 2 years was 50% for patients with AML and IA. In patients with high risk to develop IA the effect of intensified, intravenous antimycotic prophylaxis has to be proven prospectively in a cooperative and randomized setting.

Terminally differentiated CD8 cells in HIV-infected children: HIV-GAG/POL specificity and IFN-γ production.

BACKGROUND: CD8 cells are key to antiviral immunity and can be divided by phenotype into early (CD28+ CD27+), intermediate (CD28-CD27+) and terminally differentiated subsets (CD28- CD27-). Despite effective HAART there is an unexplained expansion of CD8+CD28-CD27-T cells in HIV-infected children. The cytokine production and specificity of this terminally differentiated CD8 T cell subset in chronic virus infection is unclear. PATIENTS, METHODS & RESULTS: In a cohort of 26 HIV-infected children the cytokine production of terminally differentiated CD8 cells was analyzed by intracellular staining and FACS analysis and was compared to children with chronic hepatitis B infection and to healthy children. The specificity of CD8 subsets was analyzed by staining with Gag/Pol tetramers in a cohort of 13 patients. We show that an increased production of interferon-γ in terminally and early/intermediate differentiated CD8 cell subsets after stimulation is specific for HIV-infection. The expanded population of terminally differentiated CD8+CD28-CD27- T cells does include HIV Gag/Pol specific T cells in adults but not in children. CONCLUSION: The expansion of terminally differentiated CD8 cells might be important for immunomodulation but in children it does not appear to play a role in HIV Gag and Pol specific immunity.

MHC class II deficiency cured by unrelated mismatched umbilical cord blood transplantation: case report and review of 68 cases in the literature.

MHC class II deficiency is a rare and fatal form of primary combined immunodeficiency caused by a lack of T-cell-dependent humoral and cellular immune response to foreign antigens, which can only be cured by allogenic stem cell transplantation. In the literature search, we identified 68 cases of HSCT in MHC class II deficiency in the last 14 yr. Pre- and post-transplant MHC class II deficiency is complicated by overwhelming viral infections, a high incidence of GvHD, and graft failure with a poor overall survival rate below 50%. We report an eight-month-old boy presenting with severe respiratory infections and chronic diarrhea, whose sister died at the age of four yr from septicemia. MHC II deficiency was caused by an RFXANK-mutation and treated successfully by 4/6 mismatched unrelated CBT after a myeloablative conditioning regimen based on anti-thymocyte globulin, busulfane, fludarabine, and cyclophosphamide. At present, our patient is well with full immune reconstitution 3(4/12) yr after CBT. CB may represent an alternative source of stem cells for children with MHC class II deficiency without a suitable donor.

Intracranial hemorrhage in a female leading to the diagnosis of severe hemophilia A and Turner syndrome.

BACKGROUND: Severe hemophilia A (HA) in females is a very rare phenomenon. Ignoring HA as a possible diagnose can result in fatal complications. PATIENTS: We report a 3-month old girl suffering from severe hemophilia A, presenting with intracranial hemorrhage three weeks after drop down from an infant carrier. Recurrent bleeding after neurosurgery led to the diagnosis of a HA by findings of low levels of factor VIII coagulation activity (F8:C) below 1% and normal levels of factor von Willebrand activity. METHODS: Diagnosis of hemophilia A by one stage clotting test and proof by molecular studies via long - range - PCR. Chromosome analysis in metaphases from peripheral blood lymphocytes. RESULTS: Molecular analysis showed inversion of intron 22 as the result of a maternally inherited, distal, F8 gene inversion and chromosome analyses a 45,X karyotype indicative of Turner syndrome in our patient. Diagnosis was hampered by the female sex and the presence of neither a family history of bleeding disorders nor clinical signs of Turner syndrome. CONCLUSION: Our case shows that, although uncommon in female infants, x-linked genetic bleeding disorders like HA are a possible diagnosis by very different reasons. Rare bleeding disorders, although not expected, might be present and the combined clinical, laboratory and genetic analysis are needed to establish the final diagnosis. Repetitive prolonged aPTT and clinical bleeding signs should lead to further hemostasiological investigations. An algorithm for hemostasiological investigations in case of unexplained clinical bleeding is given.

Reduced expression and defective modulation of TNF receptor/ligand family molecules on proB-ALL blasts.

BACKGROUND: There is a subgroup of pediatric patients with an immature immunophenotype of proB-ALL that still poses a therapeutic challenge, even if the overall prognosis in B cell precursor acute lymphoblasic leukemia (BCP-ALL) is very good. Due to impaired treatment response these patients are prone to suffer relapse and are thus by definition stratified into the clinically defined high risk group receiving intensified chemotherapy. Besides response to chemotherapy long term prognosis is also influenced by immunological control mechanisms. Thus, high expression of the TNF receptor CD40 has been shown to prevent particularly late relapse in BCP-ALL suggesting a pivotal role of this regulatory molecule for maintenance of the remission status. PATIENTS AND METHODS: We therefore determined the baseline expression and CD40-mediated modulation of TNF receptor and costimulatory molecules in 5 patients with proB-ALL, 8 with preB-ALL and 22 with c-ALL performing FACS analysis. We particularly compared the TNF receptor status on proB-ALL blasts to the expression on more mature preB- and c-ALL blasts. RESULTS: Here, we demonstrate for the first time a significantly lower baseline expression and CD40-induced modulation capacity of TNF receptor and costimulatory molecules in pediatric proB-ALL compared to more mature precursor B-ALL blasts. CONCLUSION: The lower expression and defective capacity of proB-ALL blasts to respond to CD40 ligand stimulation might resemble the immature feature of these blasts and besides increased chemoresistance contribute to the impaired prognosis of these patients due to escape from apoptosis and immunological control mechanisms.

Role of survivin splice variants in pediatric acute precursor B lymphoblastic leukemia.

BACKGROUND: Survivin, a member of the inhibitor of apoptosis protein (IAP) family is transiently expressed at low levels during normal hematopoesis but profoundly overexpressed in adult leukemia potentially contributing to leukemogenesis due to deregulated apoptosis and defective cell cycle control. Alternative splicing results in four different mRNA variants survivin, survivin2B, survivin-DeltaExon3 and survivin-3B, with distinct cellular localization patterns and anti-apoptotic potential. Due to co-localization of survivin and survivin-2B in the cytoplasm survivin-2B may permit interactive fine-tuning of survivin actions and moreover play an attenuating role in its anti-apoptotic function. Lack of survivin-2B is associated with disease progression of malignomas suggesting a differential role of these isoforms in tumorigenesis. PATIENTS AND METHODS: We therefore determined the expression of the functional survivin splice variants performing RT- and real-time PCR in a purely pediatric cohort of 20 patients suffering from precursor B-ALL (BCP-ALL). RESULTS: Here, we demonstrate for the first time in pediatric patients with precursor B-ALL an association between lower survivin-2B expression and affiliation to the high risk group. CONCLUSION: The idea that survivin-2B may act as natural antagonist of survivin could potentially be used in novel approaches of anti-cancer treatment by influencing the proportional expression of the different splice variants.