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Katrina Vanura,
Trang Le,
Harald Esterbauer,
Florentin Späth,
Edit Porpaczy,
Medhat Shehata,
Karin Eigenberger,
Alexander Hauswirth,
Cathrin Skrabs,
Elisabeth Krömer,
Ilse Schwarzinger,
Berthold Streubel, Christoph Steininger,
Christa Fonatsch,
Stephan Stilgenbauer,
Oswald Wagner,
Alexander Gaiger,
Ulrich Jäger
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ABSTRACT: Few data are available concerning the prevalence of autoimmune disease or chronic infections in chronic lymphocytic leukemia patients at diagnosis as well as their clinical outcome. We studied the frequency of such chronic conditions in relation to prognostic markers. A history of autoimmune disease or chronic infection was found in 21% of 186 chronic lymphocytic leukemia patients (12% in autoimmune diseases, 9% in chronic infections). Patients with a history of chronic stimulation were more likely to have unmutated IgV(H) genes (p<0.002), unfavorable or intermediate risk cytogenetics (11q, 17p deletions, trisomy 12) (p<0.001), and higher CD38 expression (p=0.004). Autoimmune conditions (n=22) were characterized by female predominance (55.0%) with a high frequency of unmutated IgV(H) (53,8%). Median time to first treatment was 83 months for the chronic stimulation group compared to 128 months for the non-chronic stimulation group (n.s.). Patients suffering from chronic conditions at chronic lymphocytic leukemia diagnosis are likely to have poor prognostic markers, particularly unmutated IgV(H) genes.
Haematologica 10/2008; 93(12):1912-6. · 6.42 Impact Factor
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ABSTRACT: We evaluated assays for the measurement of acute phase protein levels in plasma for their usefulness to identify sensitively an inflammatory response to active cytomegalovirus CMV infection in HIV-infected patients.
Plasma samples were collected from 28 CMV-seropositive patients with advanced HIV-infection (CD4-cell count <200/microl) before commencement of antiretroviral therapy. Sensitivity, specificity, and area under receiver operating characteristic curve for the selected acute phase protein assays (haptoglobin, fibronectin, high-sensitivity C-reactive protein (hs-CRP), human interleukin-6, serum amyloid A (SAA), and human lipopolysacharide binding protein) were compared with results of a CMV-specific PCR assay.
CMV viremia was detectable in 8/28 patients. Levels of SAA correlated well with those of hs-CRP (r' = 0.439, P = 0.019 (Spearman rank correlation)). Levels of SAA >3 mg/L discriminated with 100% sensitivity and 40% specificity between HIV-infected patients with and without active CMV infection. Sensitivity of fibronectin was 100% and specificity 15% at a threshold-value corresponding with the lower limit of normal values as defined by the manufacturer of the assay (>29 mg/dL). Levels of the other acute phase proteins evaluated did not correlate with detection of CMV-DNA in plasma.
Increased levels of SAA indicate sensitively an inflammatory response to active CMV infection. Use of a CMV-specific virological assay is required to confirm the specificity of a high SAA-level but may be limited to samples with high SAA-levels. Hence, screening for increased levels of SAA in patients with advanced HIV-infection may allow early identification of active CMV infection.
European journal of medical research 06/2008; 13(6):304-8. · 1.13 Impact Factor
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Wiener klinische Wochenschrift 02/2007; 119(7-8):217. · 0.81 Impact Factor
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Christoph Steininger
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ABSTRACT: Cytomegalovirus (CMV) infection is one of the most important infectious complications of solid-organ transplantation, a serious, life-threatining, opportunistic pathogen in HIV-infected patients, and may cause hearing defects and irreversible central nervous system disease in infants infected during gestation. Four drugs are currently licensed for prophylaxis, pre-emptive therapy, and treatment of CMV infection -- ganciclovir, and its oral prodrug valganciclovir, foscarnet, cidofovir, and fomivirsen. All four drugs are effective against CMV infection. Toxicities, drug-drug interactions, poor bioaailibility, and the development of drug resistance, however, are clinically relevant and common limitations of these drugs. Novel compounds are on the horizon that possibly will become useful alternatives to currently licensed drugs. Maribavir, a benzimidazol, is the most promising novel drug and closest to clinical application. Several phase II clinical trials proved its good tolerability and effectivity. Other compounds are currently evaluated in pre-clinical and phase I trials with promising preliminary data. In addition, analogs of cidofovir posess significantly improved pharmacological and virological characteristics allowing their oral administration. This review summarizes the current status in drug development and will introduce the most recent patents on this line of research.
Recent Patents on Anti-Infective Drug Discovery 02/2007; 2(1):53-72.
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ABSTRACT: Guillain-Barré syndrome (GBS) is frequently associated with the presence of CMV-specific IgM-antibodies or CMV-DNA in serum. Detection of IgM-antibodies or viremia may indicate primary infection, but also reactivation or reinfection. We identified 46 GBS patients with detectable CMV-specific IgM- or IgG-antibodies, or both. Sera from these patients were tested for the presence of CMV-specific, low-avidity IgG-antibodies, which indicate primary infection that occurred <6 months before sample collection, and for the presence of CMV-DNA by polymerase chain reaction (PCR). Primary infection was identified by the presence of low-avidity IgG-antibodies in 9/46 (20%) or by detection of IgM-antibodies in the absence of IgG-antibodies in 1/46 (2%) patients. CMV-DNA was detectable in 17/46 (37%) sera. In contrast, CMV-DNA was detected in only 2% of sera from 46 age-matched patients with neuroborreliosis. The likelihood of viremia decreased in GBS patients significantly with increasing antibody-avidity (P=0.041). Detection of IgM-antibodies correlated with that of CMV-DNA in patients with low-avidity IgG-antibodies (P=0.048) but not in those with high-avidity IgG-antibodies (P=0.543). In 45 age-matched healthy controls, low-avidity IgG-antibodies and CMV-DNA were detected in only 2% and 0% of sera, respectively. Our findings further strengthen evidence for an association between CMV infection and GBS. Primary CMV infection was identified in almost one-fourth of patients with detectable CMV-specific antibodies. Nevertheless, endogenous reactivation and reinfection have to be considered also as relevant events associated with GBS.
Journal of Neuroimmunology 02/2007; 183(1-2):214-9. · 2.96 Impact Factor
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ABSTRACT: Cytomegalovirus (CMV) infection was one of the most important opportunistic infections in HIV-infected patients before the introduction of highly active antiretroviral therapy (HAART), i.e. the combination of at least three antiretroviral drugs of different classes. Thereafter, life expectancy and quality of life increased dramatically with the persistent suppression of HIV viremia and a significant reduction in incidence of CMV disease. Nevertheless, evidence for a multitude of direct and indirect effects of CMV on HIV progression is accumulating. Even in the era of HAART, a considerable number of HIV-infected patients have a CD4 cell count below <100 mm(-3), which involves a high risk for CMV disease. The focus of the present review is on interpretation of test results, their predictive value for CMV disease, and guidance for the rational use of diagnostic assays in HIV-infected patients. Identification of patients at immediate risk for CMV disease may be accomplished by detection of CMV-DNA in leucocytes or plasma. Evidence is growing that CMV genotypes may be also relevant for the risk of CMV disease. Diagnosis of CMV disease requires in most instances demonstration of virus in biopsy specimen from the affected organ because presence of CMV in blood may not be causally related to symptoms observed. Clinical symptoms and patient characteristics are essential in the interpretation of laboratory test results and may guide the rational collection of clinical specimen and use of laboratory assays. As a consequence, a reliable diagnosis of CMV disease and early identification of patients at high risk for CMV disease requires an integrated interpretation of clinical and virological information.
Journal of Clinical Virology 09/2006; 37(1):1-9. · 3.97 Impact Factor
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ABSTRACT: To compare cytomegalovirus (CMV) strains found in cerebrospinal fluid (CSF) of patients with HIV infection and CMV encephalitis with those present in the general population with respect to genetic variation in the N terminus of the glycoprotein B (gBn)-gene.
We sequenced gBn, which is a major target of the antiviral immune response, of CMV strains present in CSF of nine HIV-infected patients with acute encephalitis, in serum of 18 immunocompetent patients with primary CMV infection, and in serum of nine HIV-infected patients without neurological illness. Sequences were compared to prototype strains and analysed by use of phylogeny.
Fourty-four percent (4/9) of gBn-sequences present in CSF did not cluster with any of the four gBn-prototype strains. Phylogenetic analysis revealed that these sequences represented two further, distinct genotypes and comparison of sequences was highly suggestive for intragenic recombination. In immunocompetent patients and HIV-infected patients without neurological illness, genotype gBn1 was the predominant strain (4/9, 44% and 8/18, 42%, respectively). Genotypes distinct from prototype strains were found in none of the immunocompetent patients and 22% (2/9) of HIV- infected patients without neurological illness.
CMV strains present in CSF of HIV-infected patients with encephalitis differ significantly from those present in the general population. Intragenic recombination of CMV may be common in patients with advanced HIV infection and a source of new CMV strains with altered biological properties.
AIDS 03/2005; 19(3):273-8. · 6.24 Impact Factor
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ABSTRACT: Varicella-zoster virus (VZV) reactivation can lead to the development of neurological disease. Diagnosis has been based on the detection of VZV DNA in cerebrospinal fluid (CSF) by PCR-based methods. The aim of this study was to determine whether the VZV DNA copy number in the CSF correlates with the course of the disease and to determine its prognostic relevance. VZV DNA was quantified in CSF samples obtained from 30 patients with neurological disease due to VZV reactivation using real time PCR, and the VZV DNA copy number was correlated to the clinical and laboratory findings for each case. Viral loads ranged from 50 copies/ml to 2.6 x 10(8) copies/ml. Significantly higher viral loads [geometric mean (GM): 7.2 x 10(4) copies/ml] were found in patients with encephalitis compared to patients with meningitis (GM: 4.1 x 10(3) copies/ml) (P=0.01, Mann-Whitney U test). In eight patients without zoster dermal lesions no significant difference in viral load (GM: 4.6 x 10(3)) was detected compared to patients exhibiting dermal lesions (GM: 2.2 x 10(4)) (P=0.14). High copy numbers of VZV DNA in CSF were clearly associated with the severity of neurological disease and none of the patients with a VZV viral load below 10(4) copies had a disease course which required intensive care.
Medical Microbiology and Immunology 02/2005; 194(1-2):7-12. · 3.83 Impact Factor
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ABSTRACT: To investigate antibody maturation and serum levels of cytomegalovirus (CMV) DNA after primary CMV infection, we studied 51 immunocompetent and 27 kidney-transplant patients. Compared with the immunocompetent patients, the transplant patients had significantly more-prolonged and -variable antibody maturation, clearly longer durations of viremia, and higher levels of CMV DNA; however, antibody maturation continued for >1 year even in immunocompetent patients. Long-term ganciclovir prophylaxis in the transplant patients was associated with either delayed immunoglobulin-G seroconversion, inhibition of antibody maturation (n=2), or immunoglobulin-class switching (n=1). In conclusion, antibody maturation continues in immunocompetent patients for a period longer than previously had been thought and is significantly delayed or even inhibited in kidney-transplant patients.
The Journal of Infectious Diseases 12/2004; 190(11):1908-12. · 6.41 Impact Factor
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ABSTRACT: Because poliomyelitis has been almost completely eradicated, Guillain-Barre syndrome (GBS) now accounts for most cases of acute flaccid paralysis. Understanding of the role of cytomegalovirus (CMV) in the pathogenesis of GBS is still very limited.
We identified 42 CMV-seropositive patients with GBS between 1998 and 2001. Cerebrospinal fluid (CSF) and serum samples obtained from these patients were tested by CMV-specific polymerase chain reaction, and the glycoprotein B (gB) segment of the detected CMV genome was analyzed. Virological findings were compared with clinical characteristics and CSF laboratory values.
CMV DNA was detected in 13 (31%) of 42 CSF samples from patients with GBS but was not detected in 42 CSF samples from age-matched control subjects with acute encephalopathy. CSF samples obtained early after the onset of GBS were significantly more likely to be positive for CMV DNA (P=.048). gB1 was the most prevalent genotype detected in patients with GBS (88%), followed by gB3 (8%) and gB2 (4%).
CMV DNA was detected frequently in CSF samples from CMV-seropositive patients with GBS, especially early during the course of the disease. The clinical significance of this finding has yet to be elucidated, but early administration of antiviral therapy might prove to be beneficial for selected patients with GBS.
The Journal of Infectious Diseases 04/2004; 189(6):984-9. · 6.41 Impact Factor
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ABSTRACT: Twenty-one patients aged 4-78 years with influenza A virus-associated acute encephalopathy were studied. Influenza A virus could be detected only in a cerebrospinal fluid (CSF) specimen obtained from 1 of 18 patients, despite the use of a highly sensitive polymerase chain reaction assay. Six patients experienced influenzal encephalopathy during the course of respiratory illness. Five of these patients had hypoprothrombinemia and 4 had increased serum creatinine levels, indicating hepatic and/or renal dysfunction. Fourteen patients experienced postinfluenzal encephalopathy <or=3 weeks after resolution of acute respiratory symptoms. In 6 patients, focal areas of high signal intensity were visible on T2-weighted magnetic resonance images of the brain. Adenovirus DNA was detected in CSF specimens obtained from 4 (36%) of 11 patients with postinfluenzal encephalopathy. Thus, influenzal encephalopathy is frequently associated with metabolic disorders, whereas postinfluenzal encephalopathy appears to have different possible etiologies.
Clinical Infectious Diseases 03/2003; 36(5):567-74. · 9.15 Impact Factor
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ABSTRACT: Virological and clinical data from 73 hepatitis C virus (HCV)-infected pregnant women who gave birth to 75 children were merged retrospectively, by logistic regression analysis, to investigate risk factors for vertical transmission of HCV. Eighty-two percent of the HCV-infected mothers were HCV-RNA-positive during pregnancy, and 10% were coinfected with human immunodeficiency virus (HIV). Nine children were HCV infected, 1 was HIV infected, but none was HIV-HCV coinfected. Among vaginal deliveries, the mean HCV load of mothers who transmitted HCV to their infants was higher than that of those who did not (8.1 x 10(5) vs. 1.4 x 10(4) copies/mL; P=.056). A reduction in umbilical cord-blood pH (relative risk, 3.9; P=.04) or the occurrence of perineal or vaginal laceration (relative risk, 6.4; P=.028) during vaginal delivery significantly increased the risk of vertical HCV transmission. In conclusion, high maternal viremia, infantile hypoxia, and intrapartum exposure to virus-contaminated maternal blood increased the risk of HCV transmission during vaginal deliveries. Consequently, cesarean section may reduce the risk of vertical HCV transmission in selected cases.
The Journal of Infectious Diseases 03/2003; 187(3):345-51. · 6.41 Impact Factor
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ABSTRACT: Serum samples from 68 immunocompetent infants (mean age, 12.6 months) with an acute adenovirus infection of the respiratory tract (39 experiencing their first adenovirus infection) were tested for the presence of adenovirus DNA, to investigate whether viral dissemination via the blood is usually present in the immunocompetent patient. Using a nested polymerase chain reaction assay, adenovirus DNA could be detected in acute-phase serum samples from 28 (41%) children. Adenovirus DNA was never found in follow-up serum samples, indicating a short period ( approximately 1 week) of viral dissemination. In children experiencing their first adenovirus infection, viral DNA could be detected in 72% of the acute-phase serum samples collected within the first week after onset of symptoms. Adenovirus DNA could also be detected in 25% of the acute-phase serum samples from patients with reinfection.
The Journal of Infectious Diseases 02/2003; 187(2):311-4. · 6.41 Impact Factor
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ABSTRACT: The antibiotic mode of action against clinical isolates of Streptococcus pyogenes and physiological factors involved in modifying the inhibitory response to the antibiotic were investigated.
We developed high-resolution respirometry for continuous monitoring of bacterial growth and inhibition kinetics. One hundred and ten clinical isolates from 90 paediatric patients were tested, including 48 isolates obtained from 28 patients with eradication failure. Respirometric inhibition curves were monitored at 4 mg/L penicillin G over a short 30 min period, corresponding to the drug's serum half-life.
None of the clinical isolates exhibited penicillin tolerance. Latency in the respirometric response of S. pyogenes to penicillin increased significantly with decreasing strain-specific respirometric growth rate. No difference in inhibition kinetics was found in vitro for isolates from patients with or without bacteriological treatment failure.
In streptococcal pharyngotonsillitis, tolerance is not a relevant concept to explain bacteriological treatment failure. Definitions of tolerance should be reconsidered in the framework of growth-dependent antibiotic susceptibility.
Journal of Antimicrobial Chemotherapy 11/2002; 50(4):517-23. · 5.07 Impact Factor
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ABSTRACT: The degrees of effectiveness of reverse transcription (RT)-PCR, virus isolation, and antigen enzyme-linked immunosorbent assay (ELISA) for the detection of influenza A virus were evaluated with nasopharyngeal swabs from 150 patients (1 week to 86 years old) with influenza A virus infection. RT-PCR had a sensitivity for influenza A virus in stock virus preparations 10(3) times higher than virus isolation and 10(6) to 10(7) times higher than ELISA. The detection rate achieved by RT-PCR in clinical samples was clearly higher (93%) than that by virus isolation (80%) and ELISA (62%). Despite low overall detection rates achieved by antigen ELISA, samples from patients younger than 5 years old yielded higher-than-average rates in this rapid assay (88%). The likelihood of negative results in the ELISA increased significantly with increasing age of the patient (P < 0.01). The degrees of effectiveness of RT-PCR and virus isolation were not influenced by the age of the patient. Neither influenza immunizations nor the interval between onset of symptoms and laboratory investigation (mean, 4.7 days; standard deviation, 3.3 days) affected results obtained by the three test systems. Our results demonstrate that the ELISA is reliable for rapid laboratory diagnosis of influenza in infants and young children, but for older patients application of RT-PCR or virus isolation is necessary to avoid false negative results.
Journal of Clinical Microbiology 07/2002; 40(6):2051-6. · 4.15 Impact Factor
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ABSTRACT: Influenza virus infection during pregnancy increases the risk of spontaneous abortion, preterm contractions, fetal compromise and early neonatal mortality. We describe a case of fetal and neonatal cardiac arrhythmia coinciding with an influenza A virus infection. Viral RNA was detected in the neonate's nasopharyngeal secretions and also in its serum, indicating influenza viremia. The cardiac arrhythmia resolved spontaneously without antiarrhythmic treatment.
Scandinavian Journal of Infectious Diseases 02/2002; 34(10):782-4. · 1.72 Impact Factor
