Hemophagocytic lymphohistiocytosis: A serious challenge for every physician

Janka, G.

doi:10.1016/j.rce.2014.05.011

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Mecanismos involucrados en la producción de disfunción orgánica." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J.L. Mostaza-Fernández, J. Guerra Laso, D. Carriedo Ule, J.M.G. Ruiz de Morales" "autores" => array:4 [ 0 => array:2 [ "nombre" => "J.L." "apellidos" => "Mostaza-Fernández" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Guerra Laso" ] 2 => array:2 [ "nombre" => "D." "apellidos" => "Carriedo Ule" ] 3 => array:2 [ "nombre" => "J.M.G." "apellidos" => "Ruiz de Morales" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2254887414000848" "doi" => "10.1016/j.rceng.2014.03.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887414000848?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256514001283?idApp=WRCEE" "url" => "/00142565/0000021400000006/v1_201407221202/S0014256514001283/v1_201407221202/es/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0014256514002203" "issn" => "00142565" "doi" => "10.1016/j.rce.2014.05.006" "estado" => "S300" "fechaPublicacion" => "2014-08-01" "aid" => "969" "copyright" => "Elsevier España, S.L." "documento" => "simple-article" "crossmark" => 0 "subdocumento" => "edi" "cita" => "Rev Clin Esp. 2014;214:315-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 693 "formatos" => array:2 [ "HTML" => 310 "PDF" => 383 ] ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "Editorial" "titulo" => "Hemophagocytic lymphohistiocytosis as a possible cause of prolonged fever, splenomegaly, and cytopenia" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "315" "paginaFinal" => "317" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Linfohistiocitosis hemofagocítica como posible cause de fiebre prolongada, espelomegalia y citopenia" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 801 "Ancho" => 1000 "Tamanyo" => 146949 ] ] "descripcion" => array:1 [ "en" => "Hemophagocytic lymphohistiocytosis. Bone marrow aspirate smear showing three macrophages displaying hemophagocytic activity (May–Grünwald–Giemsa stain; magnification 400×)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M. Machaczka" "autores" => array:1 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Machaczka" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256514002203?idApp=WRCEE" "url" => "/00142565/0000021400000006/v1_201407221202/S0014256514002203/v1_201407221202/en/main.assets" ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "Editorial" "titulo" => "Hemophagocytic lymphohistiocytosis: A serious challenge for every physician" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "318" "paginaFinal" => "319" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "G. Janka" "autores" => array:1 [ 0 => array:3 [ "nombre" => "G." "apellidos" => "Janka" "email" => array:1 [ 0 => "janka@uke.uni-hamburg.de" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Linfohistiocitosis hemofagocítica: un reto importante para los médicos" ] ] "textoCompleto" => "In the present issue of Rev Clin Esp. Mostaza-Fernández and coworkers<a class="elsevierStyleCrossRef" href="#bib0005">1</a> describe a previously healthy 16-year-old patient with an initially ordinary presentation of infectious mononucleosis which, however, rapidly progressed to fatal hemophagocytic lymphohistiocytosis (HLH), a nightmare for every physician.HLH is a clinical syndrome which develops if the immune system cannot adequately deal with a (mostly) infectious trigger. There are other potential mechanisms for inadequate immune stimulation such as cytokines produced by tumor cells, constant stimulation of the innate immune system in autoinflammatory diseases or metabolic products. Hyperactivation of lymphocytes and histiocytes leads to dangerously high cytokine levels which are detrimental for the patient. In the present case the patient developed organ failure and died from the consequences.In genetic forms of HLH there are functional defects of cytotoxic lymphocytes and natural killer (NK) cells; in acquired forms associated with an infectious trigger there may be a transient imbalance between the onslaught of a microbial agent and the capacity of the immune system to cope.Epstein-Barr virus is a potent trigger of the immune system and the leading infectious agent associated with HLH, not only in Asia where there seems to be a specific genetic susceptibility for EBV-triggered HLH, but also in Western countries. Interestingly, whereas in infectious mononucleosis EBV only infects B cells, in EBV-associated HLH the virus is either found nearly exclusively in T-cells in cases from Asia<a class="elsevierStyleCrossRef" href="#bib0010">2</a> or in equal proportions in B and T cells in white children.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>In male children and young adults with EBV-associated HLH x-linked lymphoproliferative syndrome (XLP)-1 (mutations in SH2D1A) and -2 (mutations in XIAP) have to be excluded. In XLP-1 it is always the first contact with EBV which leads to fulminant and often fatal HLH.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Patients with XLP-2 occasionally also have other viral triggers and may have a history of inflammatory bowel disease, often mistaken for Crohn's disease.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> In the present teenager familial HLH, encompassing mutations in 4 genes involved in cytotoxic granule contents and exocytosis were excluded; it is not clear whether XLP-1 and 2 were investigated as well.HLH has long been considered to be primarily a disease of infants and children. However, HLH is found in all age groups, and even genetic forms, formerly thought to be restricted to children, are now reported with increasing frequency also in adults. Notably, in a recent study on 175 adult patients with HLH, hypomorphic monoallelic or biallelic mutations in genes of familial HLH were found in 14% of the patients.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Whereas among pediatricians HLH is a well recognized entity, awareness of this clinical syndrome is less well established in physicians treating adolescents and adults. Therefore HLH often remains unrecognized or treatment may be delayed. It is important to publish reports and reviews like the present review<a class="elsevierStyleCrossRef" href="#bib0005">1</a> to heighten the awareness of HLH in physicians working in internal medicine, rheumatology, infectious diseases and on intensive care units.There is no international registry for adult patients with HLH and a network of physicians who are experienced in HLH in adults is missing. At present the diagnostic criteria and treatment elements of the international HLH studies for children are also used in adults. Recently, the HLH Steering Committee of the Histiocyte Society has formed a working group “HLH in adults” to promote knowledge about HLH among physicians treating adults and to develop guidelines for diagnosis and treatment.HLH is diagnosed by a set of clinical and laboratory parameters. Each single feature alone is unspecific, including hemophagocytosis. It is often the progression and the extent of symptoms and parameters that finally lead to the diagnosis.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>Reduced or absent NK cell activity does not differentiate between genetic or acquired HLH, although in the latter the defect is transitory. When a lymphoma has been excluded, and an autoinflammatory or autoimmune disease seems unlikely, a genetic disease has to be considered also in previously healthy adolescents and adults with HLH. Perforin, SAP (XLP1) and XIAP (XLP2) expression can be measured by flow cytometry. The CD107 degranulation assay reflects the ability of NK cells and CTLs to exocytose the contents of lytic granules into the immunological synapse<a class="elsevierStyleCrossRef" href="#bib0040">8</a>; when degranulation is reduced or absent, the candidate genes UNC13D, STXBP-2, Syntaxin-11 and RAB27A should be sequenced. Unfortunately, at present there are only few specialized labs with experience in the functional tests for HLH.Treatment of HLH remains a difficult task. Awareness of HLH should lead to prompt diagnostic measures and start of therapy, impeding the vicious attack of the cytokine storm. Assuming that the infection has to be treated first and only then HLH is a dangerous misconception. Once HLH is suspected it is mandatory to search for a treatable organism such as herpes viruses to reduce the antigenic burden and thus dampen the immune response even though additional immunosuppressive treatment is usually necessary.As the authors point out in their review,<a class="elsevierStyleCrossRef" href="#bib0005">1</a> it requires good nerves and knowledge of the pathophysiology of HLH to treat a highly febrile patient with cytopenias with immunosuppressive and cytostatic drugs. However, this approach has turned out to be life-saving for many patients. It should be emphasized, however, that HLH-directed treatment has only the aim to suppress the high cytokine levels which are responsible for the patient's symptoms and are endangering his organ functions. Judicious use of available therapeutic agents is important. When clinical symptoms and laboratory parameters have normalized, treatment should be discontinued in patients with acquired HLH. Prolonged treatment may not only lead to a reactivation of the original trigger but also to increased susceptibility toward a new triggering agent.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Familial HLH, formerly an invariably fatal disease can now be cured in a substantial proportion of children. In this entity hematopoietic stem cell transplantation (HSCT) is necessary for cure. In acquired HLH HSCT is not indicated unless the rare evolution of EBV-associated HLH into T/NK cell lymphoproliferative disease occurs or HSCT is indicated for an underlying malignancy.Hopefully, the paper by Mostaza-Fernández and coworkers<a class="elsevierStyleCrossRef" href="#bib0005">1</a> will contribute to alerting physicians to consider HLH whenever they have a patient with unremitting fever, hepatosplenomegaly and cytopenias. 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