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.

Distinguishing host responses, extensive viral dissemination and long-term viral RNA persistence in domestic sheep experimentally infected with Crimean-Congo haemorrhagic fever virus Kosovo Hoti

“…Moreover, a significant spike in lymphocyte count was detected following peak viremia, at time points ranging from 7 DPI to 9 DPI ( Figure 2 C), possibly reflecting the expansion of lymphocytes during advancing adaptive immune responses. The maintenance and expansion of lymphocytes in sheep represents a distinctive feature as lymphopenia is a hallmark of severe CCHF in humans, cynomolgus macaques and immunodeficient mice [ 12 , 30 , 31 ]. Additionally, analyzes of blood biochemical markers for liver and kidney disease identified changes that imply a transient and minor impairment in certain biochemical functions of the liver and kidney (Results and discussion S1; Figure S2).…”

Crimean-Congo Hemorrhagic Fever Virus for Clinicians—Epidemiology, Clinical Manifestations, and Prevention

“…Pediatric cases of hemophagocytic lymphohistiocytosis (HLH) secondary to CCHF have been described ( 42 , 43 ). Secondary HLH, although rare, can be associated with malignancies, severe infections, medications, and autoimmune disorders and has been thought to be secondary to a hyperinflammatory syndrome ( 44 ).…”

“…Most patients will have a combination of fever, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, a variety of neurologic symptoms, and evidence of hemophagocytosis in pathology examination of bone marrow or other tissues ( 44 ). Because of the high rates of illness and death associated with HLH, its early recognition is key for timely treatment consideration (such as corticosteroids, intravenous immunoglobulin, immunomodulators, and therapeutic plasma exchange) ( 43 , 44 ).…”

Distinguishing host responses, extensive viral dissemination and long-term viral RNA persistence in domestic sheep experimentally infected with Crimean-Congo hemorrhagic fever virus Kosovo Hoti

“…In addition, a significant spike in lymphocyte count was detected following peak viremia, at time points ranging from 7 DPI to 9 DPI (Figure 3C), possibly reflecting the expansion of lymphocytes during advancing adaptive immune responses. The maintenance and expansion of lymphocytes in sheep represents a distinctive feature as lymphopenia is a hallmark of severe CCHF in humans, cynomolgus macaques and immunodeficient mice [32,63,82]. The role of neutrophils in the control or pathogenesis of CCHFV infection is poorly understood [53,83].…”