Hurrem Bodur

Viral Load as a Predictor of Outcome in Crimean-Congo Hemorrhagic Fever

Crimean-Congo hemorrhagic fever (CCHF) is a potentially fatal disease affecting multiple organ systems. To determine the association between viral load and severity of CCHF infection, quantitative measurement of CCHF virus was performed using 1-step reverse-transcriptase polymerase chain reaction for 36 patients with CCHF infection. Viral loads ranged from 1.1x10(3) copies/mL to > or = 9.9x10(9) copies/mL. Nine (25%) of 36 patients died. In 8 of the 9 patients with fatal outcomes, viral loads were detected that were > or = 1x10(9) copies/mL, whereas in 25 of the 26 patients with nonfatal outcomes, viral loads were detected that were < 1x10(9) copies/mL (P<.001). A viral load > or = 1x10(9) RNA copies/mL can be considered to predict a fatal outcome with a positive predictive value of 80%, with 88.9% sensitivity and 92.6% specificity. We suggest that viral load is a measure of the severity of CCHF.

Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey.

OBJECTIVE The aim of this study was to evaluate the efficacy of oral ribavirin treatment in patients with Crimean-Congo haemorrhagic fever (CCHF). METHODS In 2004, all patients diagnosed with CCHF were treated with oral ribavirin, however in 2003 none of the CCHF patients had been given treatment due to lack of confirmatory diagnostic information at that time in Turkey. In this study, patients treated with ribavirin in 2004 (n=126) were compared with ribavirin-untreated CCHF patients (n=92) in 2003. Patients only with a definitive diagnosis of CCHF (clinical symptoms plus the presence of specific IgM antibodies against CCHF virus and presence of viral antigen) were included in this study. RESULTS There was no difference in the case-fatality rate between treated and untreated patients (7.1% vs. 11.9%; P>0.05). A Cox Proportional Hazards regression analysis revealed that altered sensorium and prolonged international normalized ratio were independent predictors of mortality. CONCLUSION Our results showed that oral ribavirin treatment did not improve the survival rate in CCHF patients. Ribavirin and supportive care are the only available choices for treatment of CCHF patients, but to ascertain the efficacy of ribavirin, more laboratory and observational studies are necessary and ultimately, to elucidate these conflicting results and evaluate the efficacy undoubtedly, a multicenter randomised controlled trial will be needed.

Biotypes and antimicrobial susceptibilities of Brucella isolates.

41 Brucella strains isolated from blood and cerebrospinal fluid cultures were identified to species level and biotypes detected. All of the isolates were Brucella melitensis: 2 strains of B. melitensis biotype-1 and 39 strains of B. melitensis biotype-3. In vitro activities of these strains were detected by the E test method. According to the 90% minimal inhibitory concentration (MIC90) values, the most active agent was doxycycline (MIC90 0.064 μg/ml), followed by ciprofloxacin (MIC90 0.25 μg/ml), trimethoprim–sulfamethoxazole and ceftriaxone (MIC90 0.38 μg/ml). Rifampin exhibited the highest MIC90 value (0.75 μg/ml).

Pathogenesis of Crimean-Congo Hemorrhagic Fever

Although Crimean-Congo hemorrhagic fever (CCHF) is a widespread tick-borne disease, little is known about its pathogenesis. The interaction of the virus with host cells is most likely responsible for the pathogenesis of CCHF. The main contributors are endothelial cells (ECs) and immune cells. There are 2 theories underlying the CCHF pathogenesis: One is that the virus interacts with the ECs directly and the other that it interacts indirectly via immune cells with subsequent release of soluble mediators. ECs are activated upon infection by the upregulation of soluble molecules and proinflammatory cytokines. Probably, in severe cases, deregulation and excessive release of the cytokines accompanied by endothelial activation have toxic effects, leading to increased vascular permeability, vasodilatation, and subsequently hypotension, multiple organ failure, shock, and death. Studies indicate that CCHF virus (CCHFV) also can impair the innate immune system and cause a delay in adaptive immune response, which is critical for the clearance of CCHFV. The virus has many different ways to block the immune response, leading to uncontrolled viral replication followed by systemic spread of the virus throughout the body. Partial activation of dendritic cells and macrophages, delayed induction of interferons, weak antibody response, apoptosis of lymphocytes, and hemophagocytosis are some of these tactics. However, there are many points waiting for clarification about the pathogenesis of CCHF. Although the high risk of contagiousness limits research, we need more studies to understand the CCHF pathogenesis better. Here we review the main characteristics of the pathogenesis of CCHF.

Case Management and Supportive Treatment for Patients with Crimean-Congo Hemorrhagic Fever

Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne infection which has been increasing in Turkey and European countries since the year 2000. The disease is particularly endemic in the Middle East and in some African countries. It is also seen in European countries as a travel infection. Patients with confirmed diagnosis are usually hospitalized for monitoring, while patients with good overall condition may be monitored on an outpatient basis. Hospitals that manage CCHF should have easy access to a blood bank, and tertiary care hospitals must have a well-equipped intensive care unit. Strict blood and body fluid control precautions should be started on admission to limit CCHF exposure. The follow-up period for each patient is determined based on individual clinical status and laboratory values. Since there is no specific antiviral treatment for CCHF, supportive treatment is essential. This review highlights some of the major features of case monitoring and supportive treatment in CCHF.

Neurobrucellosis in an Endemic Area of Brucellosis

Central nervous system involvement occurs less than 5% of patients with brucellosis. A prospective analysis of 73 patients with brucellosis identified 13 (17.8%) neurobrucellosis cases from February 2001 to May 2002. 10 patients had chronic meningitis and 3 acute meningitis. Two patients had only psychiatric disorders. Cranial nerve involvement was observed in 3 patients (6th, 7th and 8th nerves). Three patients had positive blood cultures and 3 others had positive cerebrospinal fluid (CSF) cultures. 12 patients had positive agglutination titres in CSF. All patients received antibiotic therapy with ceftriaxone, rifampicin and doxycycline initially, and after 1 month they were continued with rifampicin and doxycycline up to 4 months. All patients were completely cured. Hearing loss developed in 1 patient as a sequela.

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.

Effect of oral ribavirin treatment on the viral load and disease progression in Crimean-Congo hemorrhagic fever.

OBJECTIVES Crimean-Congo hemorrhagic fever (CCHF) is a lethal hemorrhagic disease. There is currently no specific antiviral therapy for CCHF approved for use in humans. In this study we aimed to investigate the effect of oral ribavirin treatment on the viral load and disease progression in CCHF. METHODS The study population was composed of patients who had a definitive diagnosis of CCHF by means of clinical presentation plus detection of viral RNA by reverse transcriptase polymerase chain reaction (RT-PCR). Ten patients who received oral ribavirin for 10 days and 40 control patients who received supportive treatment only were included in the study. Ribavirin treatment consisted of oral ribavirin 4 g/day for 4 days and then 2.4 g/day for 6 days. Viral load and hematological and biochemical laboratory parameters, which were measured daily, were analyzed. RESULTS Mean age (37.4 vs. 45.5, p=0.285), gender (male 50% vs. 62.5%, p=0.470), days from the appearance of symptoms to admission (4.3 vs.4.4 days, p=0.922), and initial complaints were similar between the ribavirin group and the control group. Upon hospital admission, mean viral load was 8.2×10⁸ copies/ml in the ribavirin group and 8.3×10⁸ copies/ml in the control group (p=0.994). During follow-up, no statistically significant differences were found between the groups with regard to the decrease in viral load, the reduction in alanine aminotransferase and aspartate aminotransferase levels, and the increase in platelet count. The case-fatality rate was 20% (2/10 patients) in the ribavirin group and 15% (6/40 patients) in the control group (p=0.509). CONCLUSION In this study, oral ribavirin treatment in CCHF patients did not affect viral load or disease progression.

A preliminary study to evaluate the effect of intravenous ribavirin treatment on survival rates in Crimean-Congo hemorrhagic fever.

CrimeaneCongo Hemorrhagic Fever (CCHF) is a serious infection with mortality rates of 15e70%. It has been an endemic disease in Turkey and large outbreaks have been seen during spring and summer seasons since 2002. Effective therapy of CCHF is not exactly described yet. Oral ribavirin has been the most applied therapy of choice in clinical practices, but the effect of this therapy on the outcome of the disease is controversial. We present here the efficacy of i.v. ribavirin therapy on survival rate among the patients with severe CCHF. This case-control study was conducted in Ankara Numune Education and Research Hospital and Sivas Cumhuriyet University Hospital between May and August 2006. Patients with suspected cases of CCHF and having severe disease were applied i.v. ribavirin therapy immediately at admission after informed consent was taken. Because the results of diagnostic tests were obtained a few days later, i.v. ribavirin therapy was initiated before laboratory confirmation. According to the laboratory test results, confirmed cases were included in the study. Patients suspected of having CCHF were selected as those who had clinical signs and symptoms, epidemiological risk factors and laboratory findings of CCHF. Confirmed cases were defined as suspected cases with positive serum RT-PCR test and/or positive serum serological test results for CCHF specific IgM by ELISA. Severe cases were defined as having at least one of the findings from splenomegaly, INR 1.4 or impaired consciousness which had been found as independent risk factors for mortality of the patients with CCHF in the study of Bakir et al. Nine patients with severe CCHF were given i.v. ribavirin immediately at admission to the hospital. Intravenous ribavirin (Virazole , Valeant Pharmaceuticals International) was supplied by Ministry of Health of Turkey. The dosage and duration of the therapy were applied according to the recommendations of the World Health Organization (WHO). It was used at the dosage of 17 mg/kg i.v. loading dose, then 17 mg/kg every 6 h for 4 days, and then 8 mg/kg every 8 h for 6 days. Sixteen severe cases of the confirmed CCHF who didn’t receive i.v. ribavirin were included in control group. Totally 25 confirmed CCHF cases with severe disease were included in the study. Nine patients receiving i.v. ribavirin in addition to supportive treatment were included in the i.v. ribavirin group while 16 patients receiving only supportive treatment were included in the control group. There were no statistically significant differences between the two groups for demographic characteristics and laboratory test results. The efficacy of i.v. ribavirin therapy was evaluated with respect to some parameters between the ribavirin group and the control group (Table 1). No statistically significant differences between the two groups were determined for fatality rate, mean duration of hospitalization and the need for transfusion of blood or blood products. Adverse effects associated with i.v. ribavirin were detected in three patients, but it didn’t need discontinuation of the therapy. Allergic maculopapular rash developed in one patient who recovered after antihistaminic therapy. Two patients had nausea and vomiting due to i.v. ribavirin and those symptoms resolved with symptomatic treatment. Ribavirin has in vitro activity against CCHF virus. It is well-absorbed from the gastrointestinal tract. Oral formulation of ribavirin is more easily available and cheaper than intravenous formulation. However, gastrointestinal tract bleeding, impaired consciousness or vomiting affects oral intake and absorption of the drug. Some of the successful results were reported with oral ribavirin. Mardani et al. from Iran reported the largest series of patients with CCHF. In this historical cohort study, the efficacy of oral ribavirin in confirmed cases of CCHF had been

Fever of Unknown Origin: Analysis of 71 Consecutive Cases

Background:Fever of unknown origin (FUO) is still an important problem in clinical practice. Evaluation of patient characteristics may clarify the utility of diagnostic tests and etiologies of FUO. Methods:Fever of unknown origin in 71 patients was investigated at Ankara Numune Education and Research Hospital in Turkey between February 2001 and December 2004. Results:Mean hospital stay and fever duration was 20.5 days and 44 days, respectively. Etiologies of FUO were as follows: infections 32 (45.1%), collagen vascular disease 19 (26.8%), neoplasm 10 (14.1%), and miscellaneous diseases 4 (5.6%). Diagnosis remained obscure in 6 patients (8.5 %). Tuberculosis was found to be 40% of the infectious causes of FUO. Mean hospital stay and fever duration were prolonged in infectious cases. Female predominance was observed in collagen vascular diseases (P = 0.047). Splenomegaly and lymphadenopathy were common in the neoplasm group (P = 0.017, P = 0.017, respectively). Erythrocyte sedimentation rate, aspartate aminotransferase, alanine aminotransferase and lactate hydrogenase levels were elevated in patients with collagen vascular diseases. Nine (12.7%) patients died during the follow-up period. Conclusions:Hospital stay and fever duration were prolonged in the infectious group of FUO patients. Infectious diseases, particularly tuberculosis, were the most important cause of FUO in our series. Tuberculosis should be kept in mind as an important etiology of FUO countries where tuberculosis is endemic.