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      Clinical and Laboratory Characteristics of Hemophagocytic Lymphohistiocytosis in Children With Severe Dengue During the 2019–2020 Outbreak in Southern Colombia

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          Abstract

          Background:

          Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled activation of inflammatory cells and an exaggerated release of cytokines. It can be triggered by different factors, including viruses, such as dengue. The objective of this study was to characterize the clinical and laboratory profiles of children with severe dengue and HLH, and to identify the risk factors for this clinical complication.

          Methods:

          An analytical study was conducted in children with severe dengue who were treated in an intensive care unit between January 2019 and March 2020. Clinical and laboratory factors were compared between patients with and without HLH.

          Results:

          HLH represented 13.4% (15/112) of children with severe dengue. Patients with HLH had a long-lasting fever (10.1 vs. 5.8 days; P = 0.012), low hemoglobin levels (7.6 vs. 10.8 g/dL; P = 0.000) and high aspartate aminotransferase values (4443 vs. 1061 U/L; P = 0.002), alanine transaminase (1433 vs. 487 U/L; P = 0.004), partial thromboplastin time (80.6 vs. 51.8 seconds; P = 0.010), prothrombin time (23.5 vs. 19.6 seconds; P = 0.024), triglycerides (333.7 vs. 223.2 mg/dL; P = 0.005), lactate dehydrogenase (4209 vs. 1947 U/L; P = 0.006), soluble CD25 (3488 vs. 1026 pg/mL; P = 0.014), and presented with higher frequency of myocarditis (66.7% vs. 38.3%; P = 0.048), hepatitis (5.3% vs. 1.3%; P = 0.014), bacterial coinfection (73.3% vs. 26.7%; P = 0.010) and fatal outcome (26% vs. 5%; P = 0.037).

          Conclusions:

          HLH is a serious life-threatening clinical complication of dengue virus infection that must be considered, particularly during outbreaks.

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          Most cited references54

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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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            Dengue

            Mortality from severe dengue is low, but the economic and resource burden on health services remains substantial in endemic settings. Unfortunately, progress towards development of effective therapeutics has been slow, despite notable advances in the understanding of disease pathogenesis and considerable investment in antiviral drug discovery. For decades antibody-dependent enhancement has been the prevalent model to explain dengue pathogenesis, but it was only recently demonstrated in vivo and in clinical studies. At present, the current mainstay of management for most symptomatic dengue patients remains careful observation and prompt but judicious use of intravenous hydration therapy for those with substantial vascular leakage. Various new promising technologies for diagnosis of dengue are currently in the pipeline. New sample-in, answer-out nucleic acid amplification technologies for point-of-care use are being developed to improve performance over current technologies, with the potential to test for multiple pathogens using a single specimen. The search for biomarkers that reliably predict development of severe dengue among symptomatic individuals is also a major focus of current research efforts. The first dengue vaccine was licensed in 2015 but its performance depends on serostatus. There is an urgent need to identify correlates of both vaccine protection and disease enhancement. A crucial assessment of vector control tools should guide a research agenda for determining the most effective interventions, and how to best combine state-of-the-art vector control with vaccination.
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              Receptors and routes of dengue virus entry into the host cells.

              Dengue is the most prevalent arthropod-borne viral disease, caused by dengue virus, a member of the Flaviviridae family. Its worldwide incidence is now a major health problem, with 2.5 billion people living in risk areas. In this review, we integrate the structural rearrangements of each viral protein and their functions in all the steps of virus entry into the host cells. We describe in detail the putative receptors and attachment factors in mammalian and mosquito cells, and the recognition of viral immunocomplexes via Fcγ receptor in immune cells. We also discuss that virus internalization might occur through distinct entry pathways, including clathrin-mediated or non-classical clathrin-independent endocytosis, depending on the host cell and virus serotype or strain. The implications of viral maturation in virus entry are also explored. Finally, we discuss the mechanisms of viral genome access to the cytoplasm. This includes the role of low pH-induced conformational changes in the envelope protein that mediate membrane fusion, and original insights raised by our recent work that supports the hypothesis that capsid protein would also be an active player in this process, acting on viral genome translocation into the cytoplasm.
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                Author and article information

                Contributors
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                Journal
                Pediatric Infectious Disease Journal
                Ovid Technologies (Wolters Kluwer Health)
                0891-3668
                2023
                March 03 2023
                June 2023
                : 42
                : 6
                : e204-e211
                Affiliations
                [1 ]Departamento de Pediatría, Facultad de Salud, Universidad Surcolombiana, Hospital Universitario Hernando Moncaleano Perdomo, Neiva, Huila, Colombia
                [2 ]Departamento de Medicina Social y Salud Familiar, Facultad Ciencias de la Salud, Universidad del Cauca, Popayán, Cauca, Colombia
                [3 ]División de Inmunología, Programa de Medicina, Facultad de Salud, Universidad Surcolombiana, Neiva, Huila, Colombia.
                Article
                10.1097/INF.0000000000003887
                fefb79b3-b80e-4b95-997b-4f3f2b4df86e
                © 2023
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