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      Tuberculosis-Associated HLH in an 8-Month-Old Infant: A Case Report and Review

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          Abstract

          Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disease, which can be mistaken for sepsis easily. Among the infectious causes that may trigger secondary HLH, tuberculosis (TBC), a rather rare pathogen nowadays, is typical. To our knowledge, this is the first case report of an infant suffering from TBC-associated HLH-induced acute respiratory failure who was treated successfully using extracorporeal membrane oxygenation. An 8-month-old boy with fever (over the last 8 wk) and pancytopenia was transferred to our institution with acute respiratory failure and for extracorporeal membrane oxygenation therapy. Bone marrow biopsy revealed hemophagocytosis. Immunological work-up for familial HLH was negative. In a desperate search for the cause of secondary HLH, an interferon-gamma release assay for TBC returned positive. However, microscopy for acid-fast bacteria as well as polymerase chain reaction for TBC were initially negative. Despite this, the child was treated with tuberculostatic therapy. TBC was finally confirmed. The child remained on extracorporeal membrane oxygenation for 28 d. Further work-up showed typical lesions of disseminated TBC. The mother was identified as the source of TBC. The boy presents with mild sequelae (fine motor skills). In infants with suspected septicemia, TBC should be considered as differential diagnosis even if the results are initially negative.

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          Most cited references56

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          HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.

          In HLH-94, the first prospective international treatment study for hemophagocytic lymphohistiocytosis (HLH), diagnosis was based on five criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). In HLH-2004 three additional criteria are introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels. Altogether five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH. HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease. In order to hopefully further improve diagnosis, therapy and biological understanding, participation in HLH studies is encouraged.
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            Infections associated with haemophagocytic syndrome

            Summary Haemophagocytic syndrome or haemophagocytic lymphohistiocytosis is a rare disease that is often fatal despite treatment. Haemophagocytic syndrome is caused by a dysregulation in natural killer T-cell function, resulting in activation and proliferation of lymphocytes or histiocytes with uncontrolled haemophagocytosis and cytokine overproduction. The syndrome is characterised by fever, hepatosplenomegaly, cytopenias, liver dysfunction, and hyperferritinaemia. Haemophagocytic syndrome can be either primary, with a genetic aetiology, or secondary, associated with malignancies, autoimmune diseases, or infections. Infections associated with haemophagocytic syndrome are most frequently caused by viruses, particularly Epstein-Barr virus (EBV). We present a case of EBV-associated haemophagocytic syndrome in a young adult with no known immunosuppression. We briefly review haemophagocytic syndrome and then discuss its associated infections, particularly EBV and other herpes viruses, HIV, influenza, parvovirus, and hepatitis viruses, as well as bacterial, fungal, and parasitic organisms.
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              Hemophagocytic syndromes--an update.

              Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome and not an independent disease. HLH represents the extreme end of a severe uncontrolled hyperinflammatory reaction that can occur in many underlying conditions. Genetic forms of HLHs are due to defects in transport, processing and function of cytotoxic granules in natural killer cells and cytotoxic T lymphocytes, and are not restricted to manifestation in childhood. Acquired forms of HLH are encountered in infections, autoinflammatory and autoimmune diseases, malignancies, acquired immune deficiency. Functional tests allow for differentiation between genetic and acquired HLH. Treatment aims at suppressing hypercytokinemia and eliminating activated and infected cells. It includes immunomodulatory and immunosuppressive agents, cytostatics, T-cell and cytokine antibodies. In genetic HLH cure can only be achieved with hematopoietic stem cell transplantation. Reduced-intensity conditioning regimens have considerably improved survival.
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                Author and article information

                Contributors
                Journal
                Front Pediatr
                Front Pediatr
                Front. Pediatr.
                Frontiers in Pediatrics
                Frontiers Media S.A.
                2296-2360
                30 October 2020
                2020
                : 8
                : 556155
                Affiliations
                [1] 1Department of Pediatric Hematology and Oncology, University Children's Hospital of Giessen , Giessen, Germany
                [2] 2Department of Pediatric Cardiology and Intensive Care, University Children's Hospital Giessen , Giessen, Germany
                [3] 3Division of Pediatric Stem Cell Transplantation, University Children's Hospital Hamburg, UKE , Hamburg, Germany
                [4] 4Center for Chronic Immunodeficiency, Institute for Immunodeficiency, Medical Center—University of Freiburg , Freiburg, Germany
                [5] 5Center of Pediatrics and Adolescent Medicine, Medical Center—University of Freiburg , Freiburg, Germany
                [6] 6Department of Anesthesiology and Intensive Care Medicine, University Children's Hospital Giessen , Giessen, Germany
                Author notes

                Edited by: Demet Demirkol, Istanbul University, Turkey

                Reviewed by: Genny Raffaeli, IRCCS Ca 'Granda Foundation Maggiore Policlinico Hospital, Italy; Şule Ünal Cangül, Hacettepe University, Turkey

                This article was submitted to Pediatric Critical Care, a section of the journal Frontiers in Pediatrics

                †ORCID: Holger Hauch orcid.org/0000-0001-6454-7783

                Christoph Neuhäuser orcid.org/0000-0002-0666-0996

                Article
                10.3389/fped.2020.556155
                7661936
                33194891
                a3ef03a8-7e71-4e26-a280-efb2c9df4936
                Copyright © 2020 Hauch, Skrzypek, Woessmann, Lehmberg, Ehl, Speckmann, Schneck, Koerholz, Jux and Neuhäuser.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 April 2020
                : 29 September 2020
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 56, Pages: 8, Words: 5130
                Categories
                Pediatrics
                Case Report

                tuberculosis,infant,hemophagocytic lymphohistiocytosis,lung failure,extracorporeal membrane oxygenation,ecmo,case report

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