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ABSTRACT: OBJECTIVE: Although the prognosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) seems to be better than HIV-associated PML, little is known about the long-term functional outcome in multiple sclerosis (MS) patients and the subsequent return of MS disease activity. We evaluated retrospectively 15 patients with natalizumab-associated PML treated at our centre. PATIENTS AND METHODS: Fifteen MS-PML patients (nine women, six men) were referred to us from adjacent local centres. The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardised treatment as described in previous work. Expanded Disability Status Scale (EDSS) and Karnofsky score in the year pre-PML, at PML-diagnosis (pre-immune reconstitution inflammatory syndrome (IRIS)) and post-PML were determined in 3-6 monthly intervals. RESULTS: The median follow-up of these 15 patients was 21.5 months. None of the 15 patients died. Three patients had a Karnofsky score of 80 or higher, nine patients between 50-70 and three patients of 40 or lower at latest examination. Eight of the 15 patients developed seizures during acute PML phase. Fifty percent of those patients were not seizure-free one year post PML, despite continuation of antiepileptic treatment. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at latest examination. CSF became virus-free in eight of the 15 patients after a median time of 4.5 months. In nine patients, disease reappeared after a median time of seven months from PML diagnosis. CONCLUSIONS: Although the clinical outcome of natalizumab-treated PML patients is much better than in patients with HIV-associated PML, this may be further improved by treatment at reference centres using standardised therapy regimens and transient intensive care if needed. Systematic studies of appropriate MS immunotherapies after PML are critically needed.
Journal of neurology, neurosurgery, and psychiatry 04/2013; · 4.87 Impact Factor
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ABSTRACT: BACKGROUND: The StratifyJCV® test is a qualitative assay to classify MS patients as anti-JC virus (JCV) antibody positive or negative. Quantification of anti-JCV antibody levels in serum and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients might add to the progressive multifocal leukoencephalopathy (PML) risk assessment. OBJECTIVE: The objective of this study is to test sera of patients in a quantitative anti-JCV antibody assay, and to compare the results with preexisting data from the StratifyJCV® test. METHODS: Sera of a total of 175 MS patients and matched non-MS-controls were tested for anti-JCV antibodies using glutathione S-transferase-tagged-VP1 as antigen. Antibody reactivity was quantified in arbitrary units using human immunoglobulin as standard. RESULTS: The comparison of our assay with StratifyJCV® showed good inter-assay agreement (kappa 0.6), and strong correlation for antibody reactivity (r(2) = 0.94). Discordant samples had low-reactive positivity, and a higher proportion (13% vs. 4%) tested positive in the StratifyJCV® test only. CONCLUSIONS: The method presented is a tool for the reliable quantification of anti-JCV antibodies, which demonstrates good agreement with results from StratifyJCV®. In contrast to StratifyJCV®, we pre-adsorbed all of the sera with BK virus (BKV) VP1 protein to reduce cross-reactivity. This step may account for a higher species-specificity of our assay. As such, our assay might be a promising additional tool for PML risk assessment.
Multiple Sclerosis 02/2013; · 4.26 Impact Factor
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ABSTRACT: BACKGROUND: Antiretroviral drugs including zidovudine (ZDV) are effective in reducing HIV mother to child transmission (MTCT), however safety concern remains. The optimal duration of postnatal ZDV has not been established in clinical studies and there is a lack of consensus regarding optimal management. The objective of this study was to investigate the effectiveness and safety of a risk adapted two week course of oral postnatal ZDV as part of a combined intervention to reduce MTCT. METHODS: 118 mother infant pairs were treated according to the German-Austrian recommendations for HIV therapy in pregnancy and in HIV exposed newborns between 2000--2010. In the absence of factors associated with an increased HIV-1 transmission risk, children were assigned to the low risk group and treated with an abbreviated postnatal regimen with oral ZDV for 2 weeks. In the presence of risk factors, postnatal ZDV was escalated accordingly. RESULTS: Of 118 mother-infant pairs 79 were stratified to the low risk group, 27 to the high risk group and 11 to the very high risk group for HIV-1 MTCT. 4 children were lost to follow up. Overall Transmission risk in the group regardless of risk factors and completion of prophylaxis was 1.8% (95% confidence interval (CI) 0.09-6.6). If transmission prophylaxis was complete, transmission risk was 0.9% (95% CI 0.01-5.7). In the low risk group receiving two week oral ZDV transmission risk was 1.4% (95% CI 0.01-8.4) CONCLUSION: These data demonstrate the effectiveness of a short neonatal ZDV regimen in infants of women on stable ART and effective HIV-1 suppression. Further evaluation is needed in larger studies.
BMC Pregnancy and Childbirth 01/2013; 13(1):22. · 2.83 Impact Factor
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ABSTRACT: BACKGROUND:: Children with petechial rash are more likely to undergo invasive diagnostics, to be treated with antibiotics for potential bacterial infection and to be hospitalized. However, viruses have also been associated with petechial rash. Nonetheless, a systematic analysis of viral infections with modern available techniques as quantitative real time polymerase chain reaction (q-PCR) in the context of petechial rash is lacking. The purpose of this pediatric study was to prospectively uncover viral pathogens that may promote the emergence of petechiae and to analyze the correlation with the clinical characteristics and course. METHODS:: We conducted a prospective study in children (0 to 18 years) presenting with petechiae and signs or symptoms of infection at the emergency department between November 2009 and March 2012. In nasopharyngeal aspirates the following viruses were analyzed by q-PCR: Cytomegalovirus, Epstein-Barr virus, parvovirus B19, Influenza A and B, parainfluenza viruses, human respiratory syncytial virus A and B, human metapneumovirus, rhinovirus, enterovirus, adenovirus, human coronavirus OC43, 229E, NL63 and human bocavirus. RESULTS:: A viral pathogen was identified in 67% of the analyzed 58 cases with petechial rash. Virus positive patients showed a significantly higher incidence of lower respiratory tract infections. Forty-one percent were viral co-infections, which were significantly younger than virus negative patients, had a higher leukocyte count and were hospitalized for a longer time. CONCLUSIONS:: A petechial rash is frequently associated viral single- and co-infections and can rapidly be identified via q-PCR.
The Pediatric Infectious Disease Journal 12/2012; · 3.58 Impact Factor
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ABSTRACT: Novel immunosuppressive/modulating therapies with monoclonal antibodies (MABs) have been associated with progressive multifocal leukoencephalopathy (PML), a potentially fatal disease of the brain caused by the JC virus. Taking the complex diagnostic testing and heterogeneous clinical presentation of PML into account, an agreed case definition for PML is a prerequisite for a thorough assessment of PML.
A working group was established to develop a standardised case definition for PML which permits data comparability across clinical trials, postauthorisation safety studies and passive postmarketing surveillance. The case definition is designed to define levels of diagnostic certainty of reported PML cases following treatment with MABs. It was subsequently used to categorise retrospectively suspected PML cases from Germany reported to the Paul-Ehrlich-Institute as the responsible national competent authority.
The algorithm of the case definition is based on clinical symptoms, PCR for JC virus DNA in cerebrospinal fluid, brain MRI, and brain biopsy/autopsy. The case definition was applied to 119 suspected cases of PML following treatment with MABs and is considered to be helpful for case ascertainment of suspected PML cases for various MABs covering a broad spectrum of indications. Even if the available information is not yet complete, the case definition provides a level of diagnostic certainty.
The proposed case definition permits data comparability among different medicinal products and among active as well as passive surveillance settings. It may form a basis for meaningful risk analysis and communication for regulators and healthcare professionals.
Journal of neurology, neurosurgery, and psychiatry 07/2012; 83(9):927-33. · 4.87 Impact Factor
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Clemens Warnke,
Thomas Dehmel,
Anita Posevitz-Fejfár,
Andrew Chan,
Achim Berthele,
Stephan Schmidt,
Judith Haas,
Helena C Kronsbein,
Florian Seitz,
Björn Tackenberg,
Mathias Mäurer,
Kathrin Gerbershagen,
Volker Limmroth, Ortwin Adams,
Hans-Peter Hartung,
Ralf Gold,
Bernhard Hemmer,
Heinz Wiendl,
Bernd C Kieseier
Multiple Sclerosis 07/2012; 18(7):1054-5. · 4.26 Impact Factor
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American Journal of Kidney Diseases 12/2011; 59(3):471-3. · 5.43 Impact Factor
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Christian Saure,
Clemens Warnke,
Fabian Zohren,
Thomas Schroeder,
Ingmar Bruns,
Ron P Cadeddu,
Christian Weigelt,
Ute Fischer,
Guido Kobbe,
Hans-Peter Hartung, Ortwin Adams,
Bernd C Kieseier,
Rainer Haas
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ABSTRACT: Treatment with natalizumab, an antibody blocking the α4-integrin, is associated with increased numbers of circulating CD34+ cells in the peripheral blood of patients with multiple sclerosis.
To determine whether natalizumab mobilizes CD34+ cells from or inhibits homing to the bone marrow (BM).
Fifty-two patients with relapsing-remitting multiple sclerosis treated with natalizumab were included. Flow cytometric analyses; polymerase chain reaction assays for JC (John Cunningham) virus DNA detection; and adhesion, migration, and apoptosis assays of immunomagnetically enriched peripheral blood and BM CD34+ cells were conducted. A comparison was made with CD34+ cells from granulocyte colony-stimulating factor-mobilized peripheral blood or steady-state BM of age- and sex-matched healthy donors.
We found adhesion and migration of peripheral blood-derived CD34+ cells to be reduced. In BM aspirates from natalizumab-treated patients, the cellularity, the proportion, and the adhesive capacity of CD34+ cells were normal. The JC virus was undetectable.
Natalizumab mediates an increase in circulating CD34+ cells by interfering with homing to the BM. Thus, CD34+ cells appear unlikely to represent a source mobilizing JC virus out of the BM in patients treated with natalizumab.
Archives of neurology 11/2011; 68(11):1428-31. · 6.31 Impact Factor
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Stefan Reuter,
Mark Oette,
Frank Clemens Wilhelm,
Bastian Beggel,
Rolf Kaiser,
Melanie Balduin,
Finja Schweitzer,
Jens Verheyen, Ortwin Adams,
Thomas Lengauer,
Gerd Fätkenheuer,
Herbert Pfister,
Dieter Häussinger
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ABSTRACT: In HIV-infected treatment-naïve patients, we analyzed risk factors for either chronic hepatitis B (HBV) infection, occult HBV infection (OHBV) or a positive hepatitis C (HCV) serostatus. A total of 918 patients of the RESINA-cohort in Germany were included in this study. Before initiating antiretroviral therapy, clinical parameters were collected and blood samples were analyzed for antibodies against HIV, HBV and HCV, HBs antigen and viral nucleic acids for HIV and HBV. Present or past HBV infection (i.e. HBsAg and/or anti-HBc) was found in 43.4% of patients. HBsAg was detected in 4.5% (41/918) and HBV DNA in 6.1% (34/554), resulting in OHBV infection in 2.9% (16/554) of patients. OHBV infection could not be ruled out by the presence of anti-HBs (50.1%) or the absence of all HBV seromarkers (25%). A HCV-positive serostatus was associated with the IVDU transmission route, non-African ethnicity, elevated liver parameters (ASL or GGT) and low HIV viral load. Replicative HBV infection and HCV-positive serostatus both correlated with HIV resistance mutations (P = 0.001 and P = 0.028). HBV and HCV infection are frequent co-infections in HIV treatment-naive patients. These co-infections influence viral evolution, clinical parameters and serological markers. Consequently, HIV patients should routinely be tested for HBV and HCV infection before initiating HIV treatment. OHBV infection constituted almost half of all HBV infections with detectable HBV DNA. Due to a lack of risk factors indicating OHBV infection, HBV diagnosis should not only include serological markers but also the detection of HBV DNA.
Medical Microbiology and Immunology 02/2011; 200(1):39-49. · 3.83 Impact Factor
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Annals of Neurology 01/2011; 69(1):215-6; author reply 216. · 11.09 Impact Factor
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Clemens Warnke,
Vsevolod Smolianov,
Thomas Dehmel,
Marcel Andrée,
Hartmut Hengel,
Fabian Zohren,
Gabriele Arendt,
Heinz Wiendl,
Rainer Haas,
Hans-Peter Hartung, Ortwin Adams,
Bernd C Kieseier
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ABSTRACT: Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment in patients with multiple sclerosis (MS). It has been hypothesized that natalizumab mobilizes JC virus (JCV)-infected haematopoietic progenitor cells mediating viraemia and subsequently this disease.
The objective of this study was to investigate peripheral haematopoietic progenitor cells for evidence of JCV DNA in MS patients treated with natalizumab.
We assessed JCV and cytomegalovirus (CMV) DNA in magnetically separated CD34+ haematopoietic progenitor cells, peripheral blood mononuclear cells and plasma of 67 natalizumab-treated patients with MS and six PML patients.
Viral DNA was not detectable in CD34+ haematopoietic progenitor or peripheral blood mononuclear cells from any sample. Two plasma samples from patients with MS while undergoing natalizumab treatment were JCV-positive. In one case clinically manifest PML developed 8 months thereafter.
Our findings do not support the hypothesis that natalizumab mobilizes JC virus-infected CD34+ cells from the bone marrow mediating JC viraemia. Notably, JC viraemia was detected in one patient with MS prior to developing clinical PML. This warrants further study.
Multiple Sclerosis 11/2010; 17(2):151-6. · 4.26 Impact Factor
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Stefan Reuter,
Mark Oette,
Frank Clemens Wilhelm,
Bastian Beggel,
Rolf Kaiser,
Melanie Balduin,
Finja Schweitzer,
Jens Verheyen, Ortwin Adams,
Thomas Lengauer,
Gerd Fätkenheuer,
Herbert Pfister,
Dieter Häussinger
Medical Microbiology and Immunology 10/2010; · 3.83 Impact Factor
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Anna Franz, Ortwin Adams,
Rhea Willems,
Linda Bonzel,
Nicole Neuhausen,
Susanne Schweizer-Krantz,
Jens U Ruggeberg,
Reinhart Willers,
Birgit Henrich,
Horst Schroten,
Tobias Tenenbaum
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ABSTRACT: The clinical significance of viral load and co-infections in children with respiratory infections is not clear.
To evaluate the correlation of viral load as well as viral and bacterial co-infections with disease severity in hospitalized children with lower respiratory tract infections (LRTIs).
This is a prospective study conducted in children admitted for LRTIs for two seasons. To determine viral and bacterial load of respiratory pathogens we performed multiplex real-time polymerase chain reaction and semiquantitative bacterial cultures on nasopharyngeal aspirates (NPA).
During the study period 244 (60%) children were hospitalized for LRTI with acute virus-induced wheezing and 160 (40%) for radiologic confirmed pneumonia. In the first NPA, viruses were identified in 315 (78%) of the 404 samples and bacteria in 198 (63.3%) of 311 samples. The viral load significantly decreased between the first and second NPA sample in most single and viral co-infections, except rhinovirus and human bocavirus infections. Viral load was inversely related to CRP in RSV infections, whereas a positive correlation was observed in adenovirus infections. Duration of hospitalization was significantly longer in RSV single infections compared to rhinovirus single infections whereas in the latter, leucocytosis and use of systemic steroids was more common. In RSV viral co-infections the presence of fever, leucocytosis, and the use of antibiotics was significantly more frequent. Positive cultures of Haemophilus influenzae dominated in RSV and rhinovirus single infections and Moraxella catarrhalis in RSV viral co-infections.
Specific viral single and co-infections as well as viral load contribute to disease severity in children with LRTIs.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 08/2010; 48(4):239-45. · 3.12 Impact Factor
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ABSTRACT: Palivizumab-resistant respiratory syncytial virus was isolated from an infant treated with palivizumab. A stable mutation at codon 276 led to a nearly complete resistance to palivizumab. Additional studies revealed a second mutation at codon 272. Further passage of the virus led to a complete loss of binding of palivizumab.
Clinical Infectious Diseases 07/2010; 51(2):185-8. · 9.15 Impact Factor
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Journal of Neurology 07/2010; · 3.47 Impact Factor
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AIDS (London, England) 01/2010; 24(2):327-8. · 4.91 Impact Factor
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New England Journal of Medicine 12/2009; 361(25):2489; author reply 2489-90. · 53.30 Impact Factor
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Ralf Winzer,
Nicolas Kanig,
Sophie Schneitler,
Stefan Reuter,
Björn Jensen,
Irmela Müller-Stöver,
Jun Oh, Ortwin Adams,
Ertan Mayatepek,
Hartmut Hengel,
Heiko Schneitler,
Dieter Häussinger
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ABSTRACT: Because of ongoing person-to-person transmission of the disease, the World Health Organization has declared a phase 6 pandemic alert for the new type of influenza A (H1N1/09). This means that the spread of the disease must be closely monitored.
At the Düsseldorf University Hospital, patients with flu-like symptoms and their contacts have been tested for the new type of influenza A since April 2009.
The first patients that tested positive for H1N1/09 were treated on 20 May 2009. By mid-September, 3372 persons underwent PCR testing of a sample obtained by deep nasal swabbing, and the results were positive in 450 (13.3%). 379 of these 450 infections, or 84.2%, had been contracted abroad. Most patients came to the hospital with flu-like symptoms within three days of becoming ill. An analysis of the first 60 patients revealed a median core temperature of 37.8 degrees C and a mildly elevated C-reactive protein concentration. All patients were treated with oseltamivir. Most of the initially symptomatic patients were asymptomatic again within 3 days; the median duration of treatment was 5 days. The median time to the first negative deep nasal swab was 4 days. No oseltamivir resistance has been found to date in our patient collective.
The clinical manifestations of the new type of influenza were still mild in the patient population that we studied up to mid-September 2009. At that time, the second wave of the pandemic had not yet begun in Germany. At present, however, the number of cases acquired within the country is on the rise.
11/2009; 106(47):770-6. · 2.92 Impact Factor
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ABSTRACT: No data on antiviral response of HBV genotypes E-H are available so far although these HBV genotypes contribute significantly to the global HBV burden. Of 49 patients with HBV genotypes E-H, 23 received interferon (IFN)-alpha, 12 nucleos(t)ide analogues and 14 patients were untreated. HBV genotype was determined by direct sequencing of the HBV S gene. Sustained virological response in IFN-treated patients was defined as normalization of ALT and decrease of HBV-DNA <4,000 IU/ml 6 months after treatment. Virological response with nucleos(t)ide analogues was assumed in patients with a HBV-DNA <200 IU/ml after 48 weeks of treatment. HBV genotype E was found in 61.2% (n = 30), HBV genotype F in 8.2% (n = 4), HBV genotype H in 10.2% (n = 5) of patients. Among patients with HBV genotype G (20.4%; n = 10) there were four HBV genotype G/A and three HBV genotype G/C co-infections. Patients had Caucasian (43%), African (55%), or Asian (2%) background. End of treatment response was 70% (16/23) and sustained virological response was 35% (8/23) for patients treated with IFN-alpha. Sustained virological response was 36% for HBV genotype E (n = 5/14), 50% for HBV genotype F or H (n = 2/4), and 20% for HBV genotype G (n = 1/5). Virus suppression at week 48 was achieved in 67% of patients treated with nucleos(t)ide analogues. According to the present preliminary data HBV genotypes E, F, and H appear to be sensitive to IFN-alpha. Lower rates of response to IFN-alpha in patients with HBV genotype G might be related to the frequent occurrence of double infection.
Journal of Medical Virology 10/2009; 81(10):1716-20. · 2.82 Impact Factor
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ABSTRACT: Respiratory viruses are the main cause of acute respiratory tract infection (ARI) in children. Real-time polymerase chain reaction (PCR) technology is highly practicable for the rapid detection of viral pathogens. The simultaneous detection of a broad spectrum of viruses enables the diagnosis and evaluation of viral coinfection in ARI.
A 1-step real-time PCR was developed for the detection of 12 respiratory viruses (10 RNA and 2 DNA viruses) in clinical samples. Clinical samples from 254 children admitted to the Departments of Pediatrics with ARI during a 10-month period were tested.
Respiratory syncytial virus (RSV) was the most frequently detected pathogen in 112 samples (44.1%), followed by human bocavirus (hBoV) in 49 (19.3%), and rhinovirus in 17 samples (6.7%). Viral coinfection was detected in 41 (16.1%) samples with RSV and hBoV being the most dominating combination (27 cases, 10.6%). Viral coinfection was found in 10 cases (17%) of children with bronchitis (n = 58) and in 7 cases (23%) of bronchiolitis (n = 30). In patients with pneumonia (n = 51), 17 cases (33%) were positive for 2 or more viral pathogens.
Simultaneous testing of respiratory viruses by real-time PCR is a suitable tool for the detection of viral coinfections. In children hospitalized because of respiratory infection viral coinfection is frequently detected with RSV and hBoV being a common combination.
The Pediatric Infectious Disease Journal 07/2008; 27(7):589-94. · 3.58 Impact Factor
