Cytokines as biomarkers of Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is a potentially severe disease caused by CCHF virus. As in other viral hemorrhagic fevers, it is considered that the course and outcome of the disease depend on the viral load and the balance among the immune response mediators, and that a fatal outcome is the result of a "cytokine storm." The level of 27 cytokines was measured in serum samples taken from 29 patients during the acute phase of the disease. Two cases were fatal. Among survivors, significant differences between severe and non-severe cases were observed in the levels of IP-10, and MCP-1, while the levels of IL-1b, IL-5, IL-6, IL-8, IL-9, IL-10, IL-15, IP-10, MCP-1, TNF-α, and RANTES differed significantly between fatal and non-fatal cases (P < 0.05). RANTES was negatively correlated with the outcome of the disease. A striking similarity with the cytokine patterns seen in Ebola virus disease was observed. A weak Th1 immune response was seen. The viral load was positively correlated with IL-10, IP-10, and MCP-1 levels, and negatively correlated with the ratio IL-12/IL-10. Especially IP-10 and MCP-1 were significantly associated with the viral load, the severity and outcome of the disease, and they could act as biomarkers and, probably, as potential targets for treatment strategies design.

Elevated chemokine levels during adult but not pediatric Crimean-Congo hemorrhagic fever.

BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral zoonosis. Clinical reports indicate the severity of CCHF is milder in children than adults. The chemokines are important chemo-attractant mediators of the host immune system. OBJECTIVES: The main aim of the study was to identify whether or not there were any differences in chemokine levels between the pediatric and adult patients and control groups, and whether there was any correlation with disease severity. STUDY DESIGN: The serum levels of select chemokines including chemokine (C-C) ligand 2 (CCL2), CCL3, CCL4, chemokine (C-X-C) ligand 8 (CXCL8), CXCL9, and granulocyte-colony stimulating factor (G-CSF) in 29 adult and 32 pediatric CCHF patients and in 35 healthy children and 40 healthy adult control groups were studied by flow cytometric bead immunoassay method. RESULTS: Great variability was detected in the serum levels of the chemokines for both the adult and pediatric patients and controls. With the exception of G-CSF, the median serum levels of CCL2, CCL3, CCL4, CXCL8, and CXCL9 were found to be significantly higher in the adult patients compared to adult controls (2364.7 vs. 761 pg/ml; 714.1 vs. 75.2 pg/ml; 88.6 vs. 25.5 pg/ml; 217.9 vs. 18.3 pg/ml; 875 vs. 352.2 pg/ml, respectively, p < 0.0001 for all comparisons). Among the chemokines the median CCL4 and G-CSF levels were significantly higher in the pediatric patients compared to pediatric controls (40.3 vs. 7.1 pg/ml, p < 0.0001; 0.1 vs. 0.1 pg/ml, p = 0.049, respectively). CONCLUSION: The results of this study showed prominent chemokine raising in adult CCHF patients compared to children CCHF patients.

Transient sinus bradycardia during the course of Crimean-Congo hemorrhagic fever in children.

Crimean-Congo hemorrhagic fever (CCHF) is an acute tick-borne viral zoonotic disease which is endemic in Turkey. Bradycardia has been reported among pediatric and adult patients with CCHF. But, it remains unclear, whether bradycardia is associated with ribavirin treatment or the severity of CCHF. In this study 26 hospitalized CCHF patients were reviewed in terms of age, gender, history of tick bite, duration of hospitalization, presence of bradycardia, laboratory features, ribavirin treatment, and blood products requirement. The demographic, clinical, laboratory and treatment characteristics of CCHF patients with or without bradycardia were compared. The mean age of the patients was 126.42±48.21 months. There were 8 female and 18 male patients. Sinus bradycardia was noted in 15 patients (mean age was 120.20±50.59 months, 5 female). Ribavirin had been administered 18 (69.2%) patients and 11 of them had bradycardia. There was not statistically significant relationships between bradycardia and ribavirin treatment (p=0.683). Furthermore the occurrence of bradycardia was not associated with disease severity according to Swanepoel severity criteria (p=0.683). We concluded that independent of the disease severity and the ribavirin treatment, transient sinus bradycardia might occur during the clinical course of CCHF in pediatric patients. For this reason clinicians should be aware of this finding and all CCHF patients should be monitored closely.

Dengue virus transmission by blood stem cell donor after travel to Sri Lanka; Germany, 2013.

Three days after donation of peripheral blood stem cells to a recipient with acute myeloblastic leukemia, dengue virus was detected in the donor, who had recently traveled to Sri Lanka. Transmission to the recipient, who died 9 days after transplant, was confirmed.

Plasma oxidative stress and total thiol levels in Crimean-Congo hemorrhagic fever.

In this study, we investigated the pro- and antioxidant status of patients with a pathogenesis of Crimean-Congo hemorrhagic fever (CCHF) in terms of their role in its pathogenesis. During the study period, 34 children and 41 adults were diagnosed with CCHF. The control group consisted of healthy age- and gender-matched children and adults. Serum levels of the total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), and plasma total thiol (TTL) were evaluated and compared between groups. The difference in mean TAC values between CCHF patients and healthy controls was not statistically significant (P > 0.05). Mean TOS, OSI, and TTL values were significantly lower in CCHF patients than in healthy controls (P < 0.001). Comparisons between the 2 groups revealed that mean TOS and OSI values were significantly lower in adults with CCHF than in their healthy counterparts (P < 0.001). Similarly, mean TTL levels were lower in both children and adults with CCHF when compared separately with healthy controls (P < 0.05). There was no significant difference in the mean serum TTL levels between children and adults with CCHF (P > 0.05). Our results suggest that TTL may play a more important role in CCHF pathogenesis than the other parameters investigated. The mean TOS and OSI values were higher in the control group than in CCHF patients.

Can the mild clinical course of crimean-congo hemorrhagic fever in children be explained by cytokine responses?

Cytokines are possibly one of the factors responsible for death due to Crimean-Congo hemorrhagic fever (CCHF). This study aimed to determine the differences between the cytokine levels in children and adult patients with CCHF; the influence of cytokines; and the severity of the course of the disease, which seems to be milder in children. Thirty-four children and 36 adult patients diagnosed with CCHF between 2010 and 2011 were included in this study. Diagnosis was performed by serology or by the polymerase chain reaction for CCHF virus. Levels of IFN-γ, TNF-α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12 p70, IL-13, IL-17A, and IL-22 were measured in all serum samples. Although the disease had a fatal course in three adult patients, there were no deaths in children. Statistically significant differences were not observed between the cytokine concentrations in the adults and children. No differences were detected between the serum cytokine levels in the children with moderate and those with a severe clinical course of the disease. In the adult patients with fatal outcome, significantly higher serum levels of IL-2, IL-5, IL-9, IL-12 p70, and IL-13 were detected as compared to the cytokine levels in patients who survived the infection. No differences were detected between the serum levels of IFN-γ, IL-1ß, IL-17A, IL-22, IL-10, IL-6, IL-4, and TNF-α in the patients who died and those who survived. Thus, the milder clinical course in children with CCHF cannot be explained by the cytokine network alone. The incomplete maturation of the immune system and timing and scale of immune responses could change the outcome dramatically.

Can hantavirus infections be predicted on admission to hospital?

The aim of this study was to investigate the predictive factors which contribute to diagnosis of hantavirus infection. One hundred patients from rural areas hospitalized with a preliminary diagnosis of hantavirus infection from different hospitals in Turkey were investigated. Hantavirus infection was confirmed in 20 patients (Group 1) using immunofluorescence and immunoblot assays at the Refik Saydam National Public Health Agency. Hantaviruses were not detected in the serum of the remaining 80 patients, other infectious and non-infectious diseases being diagnosed in this group (Group 2). Patients' demographic characteristics and clinical and laboratory data on admission were examined and compared between the two groups. Fever, proteinuria, hematuria, lethargy-weakness, and nausea-vomiting were the most frequent symptoms and findings in Group 1, seen in almost all patients. Proteinuria, hematuria, muscle pain, diarrhea/abdominal pain, hypotension, shock, and sweating were observed at significantly higher levels in Group 1 compared to Group 2. Serum urea, creatinine, uric acid, lactate dehydrogenase (LDH), aspartate transaminase (AST), alkaline phosphatase (ALP), and C-reactive protein (CRP) were significantly higher, but serum platelet counts were lower in Group 1 patients. Area beneath the receiver operating characteristics (ROC) curve analysis was used to calculate the discriminative ability of various laboratory values to identify patients with hantavirus infection. This analysis revealed that, serum CRP had a 100% negative predictive value, whilst, platelet, and creatinine had 75% and 70% positive predictive values for the diagnosis of hantavirus infection. In summary, laboratory markers used in clinical practice are of great importance predicting hantavirus infections.

A sandfly fever virus outbreak in the East Mediterranean region of Turkey.

OBJECTIVES: To report a sandfly fever virus (SFV) outbreak that occurred in Kahramanmaras Province, Turkey. METHODS: We investigated the cases of 40 patients with a history of sandfly bites and with clinical findings, who were referred to our emergency service between July and August 2010. Serum samples of 19 patients were selected and analyzed using a commercial mosaic immunofluorescence test (IFT) to detect IgM and IgG antibodies against SFV. RESULTS: Sandfly fever was diagnosed in nine patients. All cases had a history of fly bite, and the clinical findings included fever, headache, myalgia, conjunctival hyperemia, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting. In two patients, the diagnosis was confirmed by real-time PCR as sandfly Sicilian virus (SFSV). Laboratory findings in the patients included leukopenia, thrombocytopenia, and elevated levels of aspartate aminotransferase, alanine aminotransferase, creatine kinase, and C-reactive protein. All patients made a complete recovery with symptomatic treatment. CONCLUSIONS: SFV is endemic in the Mediterranean Basin and data regarding SFV activity in Turkey are limited. This is the first report of an SFV outbreak from Kahramanmaras Province, Turkey, and provides information on epidemiological, clinical, and laboratory aspects of SFV infections.

Pediatric cases of Crimean-Congo hemorrhagic fever in Turkey.

BACKGROUND: The aim of the present study was to identify the epidemiological, clinical and laboratory features of Crimean-Congo hemorrhagic fever (CCHF) virus infection in children. METHODS: Fifty children infected with CCHF virus in 2005-2010, and hospitalized in the Dr Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital in Ankara, were included. All the patients had positive IgM and/or polymerase chain reaction for CCHF virus. RESULTS: Of the 50 patients, 19 were female and 31 were male. Patients were between 8 months and 15 years of age. The majority (82%) of patients had a history of tick bite. Fever (100%), hemorrhagic symptoms (76%), nausea-vomiting (60%), tonsillopharyngitis (50%), malaise (50%), myalgia (46%) and maculopapular rash (24%) were the most common presenting clinical features. Mean platelet count on admission was 110,880/mm(3) , and the lowest was 7000/mm(3) . The mean of the lowest white blood cell count was 2860/mm(3) . Other pathological laboratory findings (asparate aminotransferase, alanine aminotransferase, lactate dehydrogenase and creatine kinase) were elevated, and prothrombin time and activated partial thromboplastin time were prolonged. Twenty-three patients (46%) were given ribavirin. No side-effect of ribavirin was seen. No patient died because of CCHF disease. CONCLUSION: CCHF virus infections are seen mostly in boys and school children and the adolescent age group. Tick bite is the major risk factor. Fever and hemorrhage are the most frequent presenting symptoms. Tonsillopharyngitis and rash on face or body are probably the most remarkable clinical findings in this disease. The CCHF disease course in Turkey may be mild in children.