Recent Progress in the Treatment of Crimean–Congo Hemorrhagic Fever and Future Perspectives

Masayuki Saijo; Shigeru Morikawa; Ichiro Kurane


Future Virology. 2010;5(6):801-809. 

In This Article

Clinical Symptoms & Pathophysiology

Patients with CCHF present with symptoms ranging in severity from fever only, or fever with flu-like symptoms, to hemorrhage with multiple organ failure, resulting in death. The time course of the typical infection consists of four phases: incubation (3–7 days), prehemorrhagic (1–7 days), hemorrhagic (2–3 days) and convalescent.[49] The incubation period is defined as the duration from exposure to CCHFV to the onset of symptoms. Incubation could differ, due to several factors, such as route of infection, dose of infected virus and age of the patients. For instance, it is reported that the average incubation time was 3.2 days when infected through a tick bite, while it was 5 and 5.6 days when infected through exposure to blood or tissue of livestock, and through exposure to blood from human cases, respectively. Patients usually have a prehemorrhagic period, which is defined as the duration from the onset of flu-like symptoms, such as fever, headache, myalgia and dizziness, but not hemorrhagic symptoms to the onset of hemorrhagic symptoms. Fever, joint pain, orbital pain, backache and headache are common symptoms. Elevation of liver enzymes has been demonstrated as well.[49]

The hemorrhagic period in typical CCHF cases rapidly develops at between 3 and 5 days from disease onset. Oliguria is a common symptom, which is presumably associated with renal failure caused by the direct influence of CCHFV infections and/or by indirect influence through hypovolemic shock. Severe cases usually progress to disseminated intravascular coagulation (DIC), leading to the exacerbation of coagulopathy.[49] Virus-associated hemophagocytic syndrome (VAHPS), presumably an important factor, has recently been reported to contribute to the clinical manifestations and severity of CCHF.[50,51] VAHPS is a rare and severe disease syndrome, characterized by fever, hepatosplenomegaly, cytopenia, elevated ferritin, lactate dehydrogenase and triglyceride levels and, most importantly, hemophagocytosis in the bone marrow, liver and lymphnodes. These events, seen in patients with VAHPS, are associated with the excessive production of various cytotokines by highly activated T-helper lymphocytes and macrophages. It was reported that VAHPS is possibly one of the major factors responsible for the high CFR rate in patients with CCHF.[50] It was reported that, of all the cytokines tested, TNF-α, soluble TNF receptor, IL-6 and IL-10 were significantly elevated in a fatal case of CCHF, but not in a nonfatal case.[52] Similar findings were also reported elsewhere.[53] Serum levels of TNF-α, IL-6 and IL-10 were measured in three fatal cases of CCHF, and were compared with those of 27 nonfatal cases. The levels of TNF-α and IL-6 were significantly higher in fatal cases than those of nonfatal cases. TNF-α production contributes to macrophage activation, resulting in hemophagocytosis. These findings support the evidence that VAHPS contributes to the pathophysiology on CCHF.

Although the number of children with CCHF is relatively small, the clinical features of CCHF in 21 children have been reported.[28] CCHF was more common in males, and approximately 70% of cases had a history of a tick bite. Fever, nausea, malaise and headache were common symptoms. Thrombocytopenia, anemia and elevated liver enzymes were also demonstrated in most cases. VAHPS was demonstrated in some children. Pulmonary hemorrhage developed in two children, and one child died.

The details of the clinical course of CCHF in children were assessed on 31 children with CCHF by researchers in Turkey.[54] Male:female ratio was 19:12. The majority of the patients (87%) had a history of a tick bite. Fever, malaise, nausea/vomiting, diarrhea, tonsillopharingitis, headache and myalgia were common symptoms. No patients died. It was documented that VAHPS was demonstrated in bone marrow aspirate in one child, indicating that VAHPS also contributes to the pathophysiology of CCHF in children.

On the contrary, the CFR of CCHF in children in Iran (26.5%; nine out of 34)[55] was reported to be higher than those in Turkey.[28,54]

Although further studies are needed, the clinical features of CCHF in children are essentially the same as those observed in adults.


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