Mustafa Gökhan Gözel

Evidence of vascular endothelial damage in Crimean-Congo hemorrhagic fever

BACKGROUND Endothelial infection has an important role in the pathogenesis of Crimean-Congo hemorrhagic fever (CCHF). In this study, we investigated the causes of vascular endothelial damage in patients with CCHF. METHODS This prospective case-controlled study was carried out at Ankara Numune Education and Research Hospital between April and September 2007. Seventy-five patients with a laboratory-confirmed diagnosis of CCHF and 88 healthy controls were enrolled in the study. Serum levels of soluble cell adhesion molecules (sICAM-1, sVCAM-1, sE-selectin, sP-selectin, sL-selectin), vascular endothelial growth factor (VEGF), and macrophage migration inhibitory factor (MIF) were investigated in these patients by quantitative sandwich ELISA technique. RESULTS In the patient group, serum levels of sVCAM-1, sL-selectin and MIF were significantly higher than in the control group; serum levels of sICAM-1, sP-selectin, sE-selectin, and VEGF were significantly lower than in the control group. Serum levels of sVCAM-1 and sICAM-1 were significantly higher in severe cases than in non-severe cases, whereas the serum level of VEGF was significantly lower. sVCAM-1 was significantly higher in non-survivors than in survivors, while serum VEGF was significantly lower in non-survivors. The optimum cut-offs of sVCAM-1 and VEGF for the prediction of mortality were 205 ng/ml and 125 ng/ml, respectively. At these cut-offs, sVCAM-1 and VEGF had a sensitivity of 100% and specificity of 42.5% and 54.5%, respectively, in identifying CCHF patients who would die from the disease. The positive predictive values were 19% and 23%, respectively; negative predictive values were 100% for both. CONCLUSION Endothelial activation can affect the course of CCHF, and vascular endothelial damage is probably indirect. Further studies are needed for general conclusions to be drawn.

Mortality indicators in pneumococcal meningitis: therapeutic implications

BACKGROUND The aim of this study was to delineate mortality indicators in pneumococcal meningitis with special emphasis on therapeutic implications. METHODS This retrospective, multicenter cohort study involved a 15-year period (1998-2012). Culture-positive cases (n=306) were included solely from 38 centers. RESULTS Fifty-eight patients received ceftriaxone plus vancomycin empirically. The rest were given a third-generation cephalosporin alone. Overall, 246 (79.1%) isolates were found to be penicillin-susceptible, 38 (12.2%) strains were penicillin-resistant, and 22 (7.1%) were oxacillin-resistant (without further minimum inhibitory concentration testing for penicillin). Being a critical case (odds ratio (OR) 7.089, 95% confidence interval (CI) 3.230-15.557) and age over 50 years (OR 3.908, 95% CI 1.820-8.390) were independent predictors of mortality, while infection with a penicillin-susceptible isolate (OR 0.441, 95% CI 0.195-0.996) was found to be protective. Empirical vancomycin use did not provide significant benefit (OR 2.159, 95% CI 0.949-4.912). CONCLUSIONS Ceftriaxone alone is not adequate in the management of pneumococcal meningitis due to penicillin-resistant pneumococci, which is a major concern worldwide. Although vancomycin showed a trend towards improving the prognosis of pneumococcal meningitis, significant correlation in statistical terms could not be established in this study. Thus, further studies are needed for the optimization of pneumococcal meningitis treatment.

Recommended precaution procedures protect healthcare workers from Crimean-Congo hemorrhagic fever virus☆

OBJECTIVES The Crimean-Congo hemorrhagic fever (CCHF) virus can spread from person to person and may cause nosocomial outbreaks among healthcare workers (HCWs). The US Centers for Disease Control and Prevention have recommended the use of personal protective equipment (PPE). We investigated the compliance of HCWs with PPE usage during the follow-up of patients, and also the number of risky contacts that occurred between patients and HCWs. We also aimed to determine the seroprevalence of CCHF virus in HCWs. METHODS This study was conducted at Cumhuriyet University Education and Research Hospital, a medical center located in a highly endemic area for CCHF where a total of 1284 confirmed CCHF patients were followed-up between 2002 and 2012. All HCWs who were at risk of CCHF virus contact and infection were included in the study. The compliance of the HCWs with PPE usage and the number of contacts that had occurred were recorded. HCW serum samples were analyzed for CCHF virus IgM and IgG by ELISA. RESULTS The total rates of PPE usage were 93.7% for gowns, 77.4% for gloves, and 38.9% for masks; the highest compliance was detected in the infectious diseases ward: 100%, 88.6%, and 82.9%, respectively. A total of four HCWs had a history of high-risk contact with contaminated material (two percutaneous exposure and two mucosal contacts), but the number of low-risk contacts was quite high. The total seroprevalence rate was only 0.53%. CONCLUSIONS Although the HCWs at our medical center have dealt with an extremely high number of CCHF patients during the last decade, the total seropositivity for CCHFV IgG was only 0.53%. This low rate may be a result of high compliance with PPE usage and also regular education programs.

Listerial rhombencephalitis in an immunocompetent young adult

Listeria monocytogenes is a common cause of central nervous system infections, especially in immunosuppressed patients, infants and elderly people. Listerial rhombencephalitis is a rare and severe infection of the brainstem that is reported to have high mortality and frequent serious sequelae for survivors. We report the case of a 19-year-old healthy male who presented with listerial brainstem infection due to Listeria monocytogenes.

Sequential determination of serum viral titers, virus-specific IgG antibodies, and TNF-α, IL-6, IL-10, and IFN-γ levels in patients with Crimean-Congo hemorrhagic fever

BackgroundAlthough there have been a number of studies on the pathogenesis of Crimean-Congo hemorrhagic fever (CCHF) recently, knowledge on this topic is still insufficient. This study aims to reveal the kinetics of serum CCHF virus (CCHFV) titers, serum levels of anti-CCHFV immunoglobulin (Ig)G, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and interferon (IFN)-γ in CCHF patients.MethodsIn total, 31 CCHF cases (11 fatal) were studied. Serum samples were obtained daily from all patients from the time of admission and continued for a 7-day hospitalization period for serologic (ELISA), virologic (real-time PCR), and cytokine (ELISA) analysis.ResultsThe mean serum CCHFV titer at admission was 5.5E + 09 copies/mL in fatal cases and 5.7E + 08 copies/mL in survivors (p < 0.001). Compared to survivors, both the mean serum levels of IL-6 and TNF-α at admission were found to be significantly increased in fatal cases. The serum levels of IL-6, TNF-α and serum CCHFV titer at admission were significantly and positively correlated with disseminated intravascular coagulation (DIC) scores (r = 0.626, p = 0.0002; r = 0.461, p = 0.009; and r = 0.625, p = 0.003, respectively). When the data obtained from the sequential determination of CCHFV titer and levels of anti-CCHFV IgG, IL-6, TNF-α, IL-10 and IFN-γ were grouped according to the days of illness, the initial serum CCHFV titer of a fatal patient was 5.5E + 09 (copies/mL) and it was 6.1E + 09 (copies/mL) in a survivor on the 2 day of illness. While significant alterations were observed in all cytokines during the monitoring period, IL-6 levels remained consistently higher in fatal cases and TNF-α levels increased in both in fatal and non-fatal CCHF cases.ConclusionsThe increased CCHFV load and higher concentrations of IL-6 and TNF-α, the presence of DIC, and the absence of CCHFV specific immunity are strongly associated with death in CCHF.

Investigation of Crimean-Congo Hemorrhagic Fever Virus Transmission from Patients to Relatives: A Prospective Contact Tracing Study

We investigated the possibility of transmission of Crimean-Congo hemorrhagic fever (CCHF) virus through respiratory and physical contact. In this prospective study, we traced 116 close relatives of confirmed CCHF cases who were in close contact with the patients during the acute phase of the infection and evaluated the type of contact between patients and their relatives. These relatives were followed for clinical signs or symptoms indicative of CCHF disease, blood samples of those with and without clinical signs were analyzed for CCHF virus immunoglobulin M and G (IgM and IgG, respectively) by enzyme-linked immunosorbent assay. No close relatives developed any signs or symptoms of CCHF and were negative for CCHF virus IgM and IgG. The results suggest that CCHF virus is not easily transmitted from person to person through respiratory or physical contact.

Evaluation of the relationship between serum levels of VEGF and sVEGFR1 with mortality and prognosis in patients with Crimean–Congo hemorrhagic fever

The most accepted view to explaining the pathogenesis of Crimean–Congo hemorrhagic fever (CCHF) is endothelial damage. This study was conducted in a University hospital to investigate the serum levels and prognostic significance of the vascular endothelial growth factor (VEGF) and its receptor, soluble fms‐like tyrosine kinase‐1 receptor (sVEGFR‐1) in CCHF. Forty‐eight consecutive hospitalized CCHF patients (grouped into severe illness and non‐severe illness) and 40 healthy adults, as controls were enrolled. There was statistically significant difference for each of VEGF (P = 0.003), and sVEGFR1 (P = 0.0001) between the patients and controls. VEGF and sVEGFR1 levels in patients with severe CCHF were found to be higher than in the control group (P = 0.0001 and P = 0.0001, respectively). A significant difference was found in VEGF (P = 0.003) and sVEGFR1 (P = 0.0001) levels when compared to patients with CCHF who died and who recovered. In patients in the group with severe illness, the sensitivity, specificity, and the area underneath the ROC curve (AUROC) belonging to those cut‐off points of VEGF and sVEGFR1 were 66.7%, 76.2%, 0.747, and 77.8%, 81%, 0.849, respectively. In non‐survivors, the sensitivity, specificity, and the AUROC belonging to those cut‐off points of VEGF and sVEGFR1 defined as 77.8%, 76.9%, 0.813, and 88.9%, 97.4%, 0.912, respectively. In conclusion, high sensitivity, specificity, and the AUROC values were found in sVEGFR1 levels especially in the severely ill and non‐survivors. Therefore, sVEGFR1 may be an important biomarker for determining the risk of severity and death as result of infection with CCHF virus. J Med. Virol. 85:1794–1801, 2013.

Community-acquired CTX-M-15-type ESBL-producing Escherichia coli meningitis: a case report and literature review.

In this report, a case of community-acquired acute bacterial meningitis (CA-ABM) caused by CTX-M-15-producing Escherichia coli in an elderly male patient was presented in the light of literature. Cultures of cerebrospinal fluid, blood, ear discharge, and stool samples yielded CTX-M-15-producing E. coli in-vitro, which was resistant to the extended-spectrum cephalosporins and ciprofloxacin and susceptible to imipenem, meropenem and amikacin. Meningitis was treated with parenteral meropenem plus parenteral and intraventricular amikacin administration. Since bacterial meningitis is a life-threatening infection, empiric antibiotic therapy with carbapenem can be started before the culture results are obtained, mainly in areas where the ESBL epidemiology is well known.

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.

Relationship between IFNA1, IFNA5, IFNA10, and IFNA17 gene polymorphisms and Crimean-Congo hemorrhagic fever prognosis in a Turkish population range.

Crimean‐Congo hemorrhagic fever (CCHF) is a fatal emerging acute viral infection. Not much is known regarding the pathogenic mechanisms and the reasons behind severe or mild disease courses in CCHF. IFN‐alpha (IFNA) is one of the essential cytokines in the immune system. Existence of single nucleotide gene polymorphisms (SNPs) in cytokines can cause susceptibility or resistance to viral agents and different clinical courses. Hence, the relationship between SNPs in genes encoding cytokines (IFNA1 ‐1823G/A (rs1332190), IFNA5 ‐2529T/A (rs758236), IFNA10 Cys20stop (rs10119910), and IFNA17 Ile184Arg (rs9298814) SNPs and disease susceptibility were investigated. The associations between SNPs and CCHF prognosis were also studied. Total 150 patients with CCHF and 170 healthy individuals were enrolled. Genotyping was performed by PCR‐RFLP methods. The frequency of IFNA1 ‐1823 (rs1332190) GG genotype was significantly higher in control subjects than CCHF patients (20% vs. 8%; P = 0.01). For IFNA17 Ile184Arg (rs9298814) polymorphism, CCHF patients having TG genotype had a higher frequency than the control subjects (38% vs. 32.4%; P = 0.039). The distribution of TT + TG genotype frequencies was also significantly higher in CCHF group than the controls (97.3% vs. 91.8%; P = 0.049). Genotype and allele frequencies for IFNA subtypes between fatal and survivors were the same (P > 0.05). Genotype and allele frequencies between severe and mild/moderate CCHF patients were also the same (P > 0.05). The results show that IFNA1 rs1332190 and IFNA17 rs9298814 SNPs may play an important role in CCHF susceptibility. Determining the existence of other connections for IFNA SNPs and CCHF severity and fatality requires further investigations. J. Med. Virol. 88:1159–1167, 2016.