Changing Disease Course of Crimean-Congo Hemorrhagic Fever in Children, Turkey

Abstract

Crimean-Congo hemorrhagic fever (CCHF), endemic in certain regions of the world, is listed as a priority disease with pandemic potential. Since CCHF was first identified in Turkey, children have been known to experience milder disease than adults. However, during the COVID-19 pandemic, we observed an unusually severe disease course, including hemophagocytic lymphohistiocytosis (HLH). We examined cytokine/chemokine profiles of 9/12 case-patients compared with healthy controls at 3 time intervals. Interferon pathway-related cytokines/chemokines, including interleukin (IL) 18, macrophage inflammatory protein 3α, and IL-33, were elevated, but tumor necrosis factor-α, IL-6, CXCL8 (formerly IL-8), and cytokines acting through C-C chemokine receptor 2 and CCR5 were lower among case-patients than controls. Interferon pathway activation and cytokines/chemokines acting through CCR2 and CCR5 improved health results among children with severe CCHF. Children can experience severe CCHF, including HLH, and HLH secondary to CCHF can be successfully treated with intravenous immunoglobulin and steroid therapy.

Keywords: CCHF; Crimean-Congo hemorrhagic fever; HLH; MIS-C; Turkey; chemokines; children; cytokines; febrile infections; hemophagocytic lymphohistiocytosis; multisystem inflammatory syndrome in children; viral hemorrhagic fevers; viruses.

Figure

Quantitative levels of cytokines/chemokines among 12 case-patients with CCHF for 3 time intervals compared with results for controls, Turkey. 1, 1st time interval, 68–72 hours after admission (black); 2, 2nd time interval, 120–132 hours after admission (red); 3, 3rd time interval, 156–180 hours after admission (blue). Controls are shown in green. Time intervals contributing to significant changes designated by number of asterisks (*). *1st time interval; **2nd time interval; ***3rd time interval. CCL, CC chemokine ligand; CXCL, C-X-C motif chemokine ligand; ENA, epithelial neutrophil-activating; HC, healthy controls; IL, interleukin; IFN, interferon; IP, IFN-γ-inducible protein; I-TAC, interferon-inducible T-cell alpha chemoattractant; RANTES, regulated upon activation, normal t cell expressed and presumably secreted; MIP, macrophage inflammatory proteins; NA, not applicable; TARC, hymus- and activation-regulated chemokine.