Randy Q. Cron Edward M. Behrens Editors Cytokine Storm Syndrome Cytokine Storm Syndrome Randy Q. Cron • Edward M. Behrens Editors Cytokine Storm Syndrome Editors Randy Q. Cron Edward M. Behrens UAB School of Medicine Perelman School of Medicine University of Alabama at Birmingham University of Pennsylvania Birmingham, AL, USA Philadelphia, PA, USA ISBN 978-3-030-22093-8 ISBN 978-3-030-22094-5 (eBook) https://doi.org/10.1007/978-3-030-22094-5 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. 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This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland This textbook was necessitated by the broadening recognition of cytokine storm syndromes (CSS) and their import and impact on health worldwide. We dedicate this to the clinicians and scientists who explore CSS and to the patients and their families who allow us to learn how best to diagnose and treat CSS. We also would like to dedicate this work to our families who supported us during the process of preparing this textbook. Foreword The coeditors of the textbook Doctors Cron and Behrens have bravely embarked on the ambitious course of bringing together a group of international experts to dissect the current knowledge of cytokine storm syndrome (CSS) underlying both the pri- mary (p) and secondary (s) haemophagocytic lymphohistiocytosis (HLH). The resulting state-of-the-art chapters cover the historic background, clinical and labo- ratory features, criteria for diagnosis, and current classification (Part I), pathophysi- ology (genetics, immunology, and murine models—Parts II, III, VII, respectively), different potential triggers (infections, rheumatic, various others—Parts IV, V, VI, respectively), and current treatment options (Part VIII). Raising awareness of the CSS within the wide physician community is one of the textbook editors’ major goals. The term ‘cytokine storm’ refers to an activation cascade of auto-amplifying cytokine production due to unregulated host immune response to different triggers, resulting in clinical presentation of a desperately ill patient with unremitting fever, hepatosplenomegaly, progressive liver failure with coagulopathy, cytopenias, hyperferritinemia, and often central nervous system (CNS) involvement. If this constellation of clinical features is not recognised and if adequate treatment is not promptly instituted, progression to multiple organ failure vii viii Foreword (MOF) and eventual death is inevitable. Infections are the earliest recognised and by far the most common cause; other triggers include malignancy; rheumatic (autoim- mune and autoinflammatory) disorders—where the process is termed macrophage activation syndrome (MAS)—as well as iatrogenic insults such as graft-versus-host disease (GvHD) in the course of haematopoietic stem cell transplantation (HSCT); and administration of different immunotherapeutic agents (e.g. monoclonal anti- bodies, chimeric antigen receptor (CAR) T cells, etc.). Since the initial reports in the early 1990s of ‘cytokine release syndrome’ [1] and/or ‘cytokine storm syndrome’ [2] and the discovery of a number of underly- ing genetic mutations affecting primarily T and natural killer (NK) lymphocyte cytotoxicity in young children with rare hereditary diseases of immune dysregu- lation, the familial (primary) haemophagocytic lymphohistiocytosis (pHLH) [3], the understanding of the underlying pathogenesis continues [4]. It is well docu- mented that other mechanisms besides failure of lymphocyte cytotoxicity, classi- cal for pHLH-a ssociated gene mutations, can lead to hyperinflammation, including primary macrophage activation (by accumulation of metabolites, con- stitutive activation, or dysregulation of inflammasomes), impaired control of common viruses (by impaired lymphocyte signalling, development, or function), defects in interferon signalling, or impaired autophagy [5]. Nevertheless, all patients lacking pHLH-associated gene mutations are still classified as sHLH, even those with proven genetic predisposition, such as an increasing number of other primary (genetic) immunodeficiency disorders (PID) (e.g. severe combined and combined immunodeficiency (SCID and CID, respectively), chronic granu- lomatous disease (CGD), autoimmune lymphoproliferative syndrome (ALPS), etc.) and certain hereditary metabolic disorders (e.g. lysosomal acid lipase defi- ciency, lysinuric protein intolerance). Moreover, the genetic predisposition to sHLH has been supported by an animal model implying that select combined variants in pHLH-associated genes (e.g. mutational burden) may be clinically relevant and by reports of variations of pHLH-associated gene mutations (e.g. biallelic hypomorphic mutations, mono-allelic or digenic mutations in genes affecting lymphocyte cytotoxicity) found in patients with underlying rheumatic disorders and malignancy, with or without MAS [6]. However, recent report of whole-exome sequencing (WES) study of a large patient group did not support a digenic model of susceptibility for HLH as the majority of such variants were present in general population. Nevertheless, the study pointed to the association between HLH and genetic variants in a group of dysregulated immune activation or proliferation (DIAP) genes, most of yet unknown significance but including significant associations for mono-allelic and biallelic variants in some of the inflammasome genes (e.g. NLRC4 and NLRP12, and NLRP4, NLRC3, and NLRP13, respectively) [7]. The precise genetic diagnosis is primarily of major clinical importance as that information, alongside the progress in understanding the nature of the initiation and progression of the systemic (hyper)inflammatory process characterising CSS, Foreword ix enables clinical intervention relevant to and specific for individual patients, fur- ther paving the way towards precision medicine era [8]. This knowledge is already in practice, influencing important clinical decisions regarding appropriate treat- ments, such as targeting different and specific non- or malfunctioning pathways (e.g. failure of T- and NK-cell cytotoxicity, uncontrolled macrophage activation, overproduction of an array of different cytokines including interferon-gamma (IFN-γ), interleukin (IL)-1, IL-6, IL-18, tumour necrosis factor (TNF) [5]) and identifying the potential novel targets [9], as well as the role of allogeneic HSCT [10]. The multidisciplinary team (MDT) approach to the complex clinical man- agement is paramount [11], both for recognising the underlying cause and for deciding about the most appropriate and specific treatment as demonstrated by our recent experience with a 2-year-old patient who initially presented to the haematology team with acute EBV-related liver and bone marrow failure and CNS involvement but failed to respond to HLH-2004 protocol. During the 2-month-long dramatic clinical course in paediatric intensive care unit, the diag- nosis was confirmed as X-linked lymphoproliferative syndrome type 1 (XLP1), and in spite of escalating treatment regimen with an arsenal of classic (prolonged HLH-2004 protocol, anti-T-lymphocyte globulin (ATG)) and newly (at the time) emerging therapies (including rituximab, alemtuzumab, infliximab, and anakinra—the high-dose ‘Cron regimen’), the immunology team only achieved transient and incomplete remission of the HLH process. However, and most importantly, this offered the window of opportunity for a curative allogeneic HSCT using a reduced-intensity conditioning regimen with alemtuzumab, treo- sulfan, and fludarabine [12]. As several overlapping themes are reviewed by the different authors, certain degree of repetition was inevitable. However, many topics, for example, the one on historic background, experienced and presented by the authors who ‘lived through the journey’ only enrich the reader’s insight into the prolonged process, lasting over decades, to firstly recognise and subsequently define HLH as a new disease entity and to understand the underlying cytokine storm as ‘a co-morbidity of another con- current immunologic disease process’ (Cron RQ and Behrens EM, Preface). No sur- prise that I reflected on my first experience with this devastating disease: back in the early 1980s with a trainee in Belgrade, former Yugoslavia, I looked after a dramati- cally sick young girl with very active systemic juvenile idiopathic arthritis (sJIA) who developed florid Epstein-Barr virus (EBV) infection—not that I knew at the time, of course, but only realised decades later that she was dying from macrophage activation syndrome! Paradoxically, some of the challenges looming on the horizon may be directly induced by the unprecedented progress presented in this book. The precise genetic diagnosis [3, 13] may precipitate the ‘information storm’, and finding the right way out may not be easy. What is the actual clinical diagnosis of a complex phenotype including HLH features caused by multiple gene mutations defining different clini- cal entities [14]? What is the best management plan for asymptomatic children with x Foreword underlying HLH confirmed by gene mutation (e.g. healthy siblings of a patient) [15]? The progress nevertheless continues, both in understanding the pathogenesis [3–5, 16] and in approaching the management [8, 11, 12] of CSS, irrespective of the numerous possible underlying causes. 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