Hemophagocytic lymphohistiocytosis as a possible cause of prolonged fever, splenomegaly, and cytopenia.

EDITORIAL Hemophagocytic lymphohistiocytosis as a possible cause of prolonged fever, splenomegaly, and cytopenia Linfohistiocitosis hemofagocítica como posible cause de fiebre prolongada, espelomegalia y citopenia Hyperinflammatory response may be one of the causes for a long-lasting unexplained fever in children and adults. 1 Clinical syndrome of the exaggerated inflammatory reaction is called hemophagocytic lymphohistiocytosis (HLH) or hemophagocytic syndrome. 1,2 Although HLH is an aggressive and potentially life-threatening disorder, it is hardly known among many physicians. 3 It has been proposed that the clinical manifestation of HLH is caused by an uncontrolled activation and proliferation of immune cells in response to variety of congenital and acquired factors. 1 Macrophages and cytotoxic CD8+ lymphocytes massively release various inflammatory Aforementioned phenomena together with an impaired cytotoxic function of natural killer (NK) cells and CD8+ lymphocytes, result in the hyperinflammatory phenotype. Depending on the etiology, HLH can be divided into genetic (primary) and acquired (secondary) forms. 1-3 Inherited familial forms of HLH (FHL) usually present in infancy or early childhood (80% of cases). However, the first episode of FHL can occur at any point in a patient's life (i.e., both fetuses and adults). 6-9 Therefore, the possibility of late-onset FHL in adults with HLH cannot be univocally excluded before tests of NK/T cell degranulation and activity, as well as genetic testing, is performed. Perforin gene mutation as a cause of HLH was first described in 1999. 10 Over the next few years, mutations in genes PRF1 (FHL-2), UNC13D (FHL-3), STX11 (FHL-4) and STXBP2 (FHL-5) were identified as responsible for the development of genetic HLH. 11-14 Their common feature is impairment in the production of proteins necessary for the proper functioning of granule cytotoxicity. HLH may occur in very rare immune deficiency syndromes associated with albinism (i.e., Griscelli syndrome 2, Chédiak-Higashi syndrome , and Hermansky-Pudlak syndrome type II, which are caused by mutations in genes RAB27A, LYST, and AP3B1, respectively) and lymphoproliferative syndromes associated with chromosome X (XLP1 and XLP2, which are caused by mutations in genes SH2D1A and BIRC4, respectively). 1 Other inherited conditions that can present with HLH are some known immunodeficiency syndromes such as X-linked SCID, X-linked hypogammaglobulinemia, Wiskott-Aldrich syndrome, and DiGeorge syndrome del (22q11.2). 1 Recently, mutations in IL-2-inducible T cell kinase (ITK), CD27 and magnesium transporter gene (MAGT1) have been reported to be associated with EBV-associated lymphoproliferation, lymphoma and HLH. In FHL, the only manifestation of the disease is HLH. In …