Abstract
The pathogenesis of severe dengue remains unclear, particularly the mechanisms underlying the plasma leakage that results in hypovolaemic shock in a small proportion of individuals. Maximal leakage occurs several days after peak viraemia implicating immunological pathways. Skin is a highly vascular organ and also an important site of immune reactions with a high density of dendritic cells (DCs), macrophages and T cells. We obtained skin biopsies and contemporaneous blood samples from patients within 24 hours of onset of dengue shock syndrome (DSS), and from healthy controls. We analyzed cell subsets by flow cytometry, and soluble mediators and antibodies by ELISA; the percentage of migratory CD1a+ dermal DCs was significantly decreased in the DSS patients, and skin CD8+ T cells were activated, but there was no accumulation of dengue-specific antibodies. Inflammatory monocytic cells were not observed infiltrating the skin of DSS cases on whole-mount histology, although CD14dim cells disappeared from blood.
Highlights
The pathogenesis of severe dengue remains unclear, the mechanisms underlying the plasma leakage that results in hypovolaemic shock in a small proportion of individuals
A cascade of immunological mediators generated in response to the infection are thought to alter microvascular function in some way, but debate continues at to which immune cells and/or mediators are primarily involved, and how these factors interact with the microvasculature
We addressed the question whether myeloid cell activation and mobilisation was apparent in the skin during acute dengue, and whether this could be a potential driver or amplifier of vascular pathology
Summary
The pathogenesis of severe dengue remains unclear, the mechanisms underlying the plasma leakage that results in hypovolaemic shock in a small proportion of individuals. Symptomatic dengue affects an estimated 100 million people worldwide each year[1] Depending on factors such as age, pre-existing flavivirus immunity, and the dengue virus (DENV) serotype responsible for the current infection, 1–7% of symptomatic individuals develop severe disease[2]. This manifests with a vascular leakage syndrome characterized by hemoconcentration and serosal effusions, usually accompanied by thrombocytopenia and a coagulopathy[3,4,5]. Characteristic Age (years) Male sex BMI (kg/m2) Illness day at enrolment (days) Time from DSS onset to biopsy (hours) Overall percentage hemoconcentration (%) Minimum platelet count* (109/L) Required parenteral colloid therapy Dengue diagnostics PCR Confirmed Dengue IgM & IgG positive at presentation on day 6 (2 cases) or 7 (2 cases) Dengue RT-PCR positive Dengue 1 Dengue 2 Dengue 3 Dengue 4 Immune status Secondary infection
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