Publications by authors named "Daniela Huzly"

40 Publications

Prevalence of SARS-CoV-2 Infection in Children and Their Parents in Southwest Germany.

JAMA Pediatr 2021 Jan 22. Epub 2021 Jan 22.

Institute of Virology, University Medical Centre and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.

Importance: School and daycare closures were enforced as measures to confine the novel coronavirus disease 2019 (COVID-19) pandemic, based on the assumption that young children may play a key role in severe acute respiratory coronavirus 2 (SARS-CoV-2) spread. Given the grave consequences of contact restrictions for children, a better understanding of their contribution to the COVID-19 pandemic is of great importance.

Objective: To describe the rate of SARS-CoV-2 infections and the seroprevalence of SARS-CoV-2 antibodies in children aged 1 to 10 years, compared with a corresponding parent of each child, in a population-based sample.

Design, Setting, And Participants: This large-scale, multicenter, cross-sectional investigation (the COVID-19 BaWü study) enrolled children aged 1 to 10 years and a corresponding parent between April 22 and May 15, 2020, in southwest Germany.

Exposures: Potential exposure to SARS-CoV-2.

Main Outcomes And Measures: The main outcomes were infection and seroprevalence of SARS-CoV-2. Participants were tested for SARS-CoV-2 RNA from nasopharyngeal swabs by reverse transcription-polymerase chain reaction and SARS-CoV-2 specific IgG antibodies in serum by enzyme-linked immunosorbent assays and immunofluorescence tests. Discordant results were clarified by electrochemiluminescence immunoassays, a second enzyme-linked immunosorbent assay, or an in-house Luminex-based assay.

Results: This study included 4964 participants: 2482 children (median age, 6 [range, 1-10] years; 1265 boys [51.0%]) and 2482 parents (median age, 40 [range, 23-66] years; 615 men [24.8%]). Two participants (0.04%) tested positive for SARS-CoV-2 RNA. The estimated SARS-CoV-2 seroprevalence was low in parents (1.8% [95% CI, 1.2-2.4%]) and 3-fold lower in children (0.6% [95% CI, 0.3-1.0%]). Among 56 families with at least 1 child or parent with seropositivity, the combination of a parent with seropositivity and a corresponding child with seronegativity was 4.3 (95% CI, 1.19-15.52) times higher than the combination of a parent who was seronegative and a corresponding child with seropositivity. We observed virus-neutralizing activity for 66 of 70 IgG-positive serum samples (94.3%).

Conclusions And Relevance: In this cross-sectional study, the spread of SARS-CoV-2 infection during a period of lockdown in southwest Germany was particularly low in children aged 1 to 10 years. Accordingly, it is unlikely that children have boosted the pandemic. This SARS-CoV-2 prevalence study, which appears to be the largest focusing on children, is instructive for how ad hoc mass testing provides the basis for rational political decision-making in a pandemic.
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http://dx.doi.org/10.1001/jamapediatrics.2021.0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823424PMC
January 2021

Characterization of pre-existing and induced SARS-CoV-2-specific CD8 T cells.

Nat Med 2021 01 12;27(1):78-85. Epub 2020 Nov 12.

Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Emerging data indicate that SARS-CoV-2-specific CD8 T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals. However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8 T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8 T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8 T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8 T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8 T cells exhibited functional characteristics comparable to influenza-specific CD8 T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8 T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41591-020-01143-2DOI Listing
January 2021

COVID-19 in a Severely Immunosuppressed Patient With Life-Threatening Eosinophilic Granulomatosis With Polyangiitis.

Front Immunol 2020 28;11:2086. Epub 2020 Aug 28.

Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Immunosuppressive therapies increase the susceptibility of patients to infections. The current pandemic with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compels clinicians to develop recommendations for successful clinical management and surveillance of immunocompromised patients at high risk for severe disease progression. With only few case studies published on SARS-CoV-2 infection in patients with rheumatic diseases, we report a 25-year-old male who developed moderate coronavirus disease 2019 (COVID-19) with fever, mild dyspnea, and no major complications despite having received high-dose prednisolone, cyclophosphamide, and rituximab for the treatment of highly active, life-threatening eosinophilic granulomatosis with polyangiitis (EGPA).
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http://dx.doi.org/10.3389/fimmu.2020.02086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484740PMC
October 2020

Rotavirus outbreak among adults in a university hospital in Germany.

J Clin Virol 2020 08 2;129:104532. Epub 2020 Jul 2.

Institute of Virology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Background: Rotaviruses are the main cause of acute viral gastroenteritis in children under five years of age. Adults seem to be less frequently affected by rotaviruses most likely due to partial immunity resulting from prior infections.

Objectives: To describe a hospital-associated outbreak of rotavirus infections among adults.

Study Design: Routine diagnostics and contact screening of symptomatic patients hospitalized at the university hospital of Freiburg. For rotavirus-positive patients, we performed rotavirus genotyping of all rotavirus RT-PCR positive samples and phylogenetic analysis.

Results: Between December 2016 and April 2017 routine diagnostics showed an unexpectedly high number of rotavirus infections among adults with the exception of one pediatric case. In total, 32 temporal-associated cases were identified. Among these, two asymptomatic cases were detected. Genotyping showed that all isolates belonged to rotavirus G2P[4]. Phylogenetic analysis confirmed an outbreak. Infection prevention and control successfully contained further spread.

Conclusions: Infections with rotavirus are rare among adults but may spread between patients making timely recognition of rotavirus infections important for infection control. Rapid phylogenetic analysis is crucial for proactive infection control.
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http://dx.doi.org/10.1016/j.jcv.2020.104532DOI Listing
August 2020

Ad hoc laboratory-based surveillance of SARS-CoV-2 by real-time RT-PCR using minipools of RNA prepared from routine respiratory samples.

J Clin Virol 2020 06 22;127:104381. Epub 2020 Apr 22.

Institute of Virology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Background: A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China in late 2019 and subsequently caused a pandemic. Surveillance is important to better appreciate this evolving pandemic and to longitudinally monitor the effectiveness of public health measures.

Objectives: We aimed to provide a rapid, easy to establish and costeffective laboratory-based surveillance tool for SARS-CoV-2.

Study Design: We used minipools of RNA prepared from nucleic acid extractions of routine respiratory samples. We technically validated the assay and distributed the protocol within an informal network of five German university laboratories.

Results: We tested a total of 70 minipools resembling 700 samples shortly before the upsurge of cases in Germany from 17.02.2020 to 10.03.2020. One minipool reacted positive and after resolution one individual sample tested SARS-CoV-2 positive. This sample was from a hospitalized patient not suspected of having contracted SARS-CoV-2.

Conclusions: Our approach of a laboratory-based surveillance for SARSCoV-2 using minipools proved its concept is easily adaptable and resource-saving. It might assist not only public health laboratories in SARS-CoV-2 surveillance.
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http://dx.doi.org/10.1016/j.jcv.2020.104381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175872PMC
June 2020

WHO international standard for anti-rubella: learning from its application.

Lancet Infect Dis 2020 01 6;20(1):e17-e19. Epub 2019 Sep 6.

WHO, Geneva 1211, Switzerland; Paul-Ehrlich-Institute, Langen 63225, Germany.

The WHO international standard for anti-rubella was first established in the 1960s when clinical diagnostics were in their infancy. Since the endorsement of the first international standard for anti-rubella IgG (RUBI-1-94), new rubella vaccines have been developed and global coverage of rubella vaccination has increased. Methods used to measure concentrations of anti-rubella IgG have also evolved to rapid, high-throughput binding assays, which have replaced often cumbersome and highly technical functional assays. During this timeframe, the protective concentration of antibody was set at 10 IU/mL by extrapolation of functional assay correlates; however, the subpopulation of antibodies within a polyclonal serum that confer protection remained undefined. Anti-rubella assays have variable formats, including antigens used, such that the same clinical sample tested on different assays can report different values with potentially devastating consequences, such as recommending to terminate pregnancy. WHO convened a meeting of experts in the rubella field to discuss the use of RUBI-1-94 and the potential future role of this international standard. The main conclusions of this meeting questioned the appropriateness of 10 IU/mL as the cutoff for protection and acknowledged the continuing role of RUBI-1-94 as a reference preparation to address analytical sensitivity and assay variation.
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http://dx.doi.org/10.1016/S1473-3099(19)30274-9DOI Listing
January 2020

The MRZ-Reaction and Specific Autoantibody Detection for Differentiation of ANA-Positive Multiple Sclerosis From Rheumatic Diseases With Cerebral Involvement.

Front Immunol 2019 19;10:514. Epub 2019 Mar 19.

Department of Neurology and Neurophysiology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.

Rheumatic diseases with involvement of the central nervous system (RDwCNS) may mimic multiple sclerosis (MS). Inversely, up to 60% of MS-patients have antinuclear autoantibodies (ANAs) and may be misdiagnosed as RDwCNS. The detection of antibodies against extractable nuclear antigens (ENA) and oligoclonal bands (OCB) are established valuable diagnostic tools in the differential diagnosis of RDwCNS and MS. The MRZ-reaction (MRZR) is defined by three antibody indices (AIs) against neurotropic viruses and is frequently positive in MS. To investigate the added value of MRZR combined with testing for antibodies against ENAs and OCB detection to distinguish RDwCNS from ANA positive MS. MRZR was evaluated in RDwCNS ( = 40) and 68 ANA positive MS-patients. Two stringency levels, MRZR-1 and MRZR-2 (at least one respectively two of three AIs positive) were applied. Autoantibody testing included ANA plus ENA and anti-dsDNA antibodies, antiphospholipid antibodies, and anti-neutrophil cytoplasmic antibodies. Most of the RDwCNS patients ( = 32; 80%) suffered from systemic lupus erythematosus. Within the RDwCNS group 20% had a positive MRZR-1 and 8.5% a positive MRZR-2 compared to 80.9 and 60%, respectively within the MS-group ( < 0.0001 for both comparisons). Oligoclonal bands were found in 28.6% of the RDwCNS patients and 94.3% of the MS-patients ( < 0.0001). Conversely, autoantibodies to specific nuclear antigens or phospholipids were found more frequently in RDwCNS. A positive MRZR in conjunction with the absence of ENA autoantibodies distinguished MS from RDwCNS with high specificity (97.5%). We suggest combining MRZR, OCBs, and specific autoantibody diagnostics to differentiate RDwCNS from MS.
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http://dx.doi.org/10.3389/fimmu.2019.00514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433788PMC
September 2020

Abdominal pain, unconsciousness, and skin rash after lung transplantation.

Transpl Infect Dis 2018 Dec 21;20(6):e12993. Epub 2018 Sep 21.

Faculty of Medicine, Department of Anesthesiology and Critical Care, Medical Center - University of Freiburg, Freiburg, Germany.

Long-term success of lung transplantation is limited by allograft dysfunction and frequent infections. Varicella zoster virus infection (VZV) is one of the most common opportunistic infections among solid organ transplantation recipients. However the occurrence of visceral involvement or disseminated disease, as seen after bone marrow transplantation, is rare. We report a case of a 59-year-old woman who underwent double-lung transplantation with a fatal visceral and disseminated varicella zoster virus infection.
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http://dx.doi.org/10.1111/tid.12993DOI Listing
December 2018

The MRZ reaction and a quantitative intrathecal IgG synthesis may be helpful to differentiate between primary central nervous system lymphoma and multiple sclerosis.

J Neurol 2018 May 6;265(5):1106-1114. Epub 2018 Mar 6.

Medical Care Unit Konstanz, Luisenstraße 7g, 78464, Constance, Germany.

Some patients with primary central nervous system lymphoma (PCNSL) may initially present with similar clinical, magnetic resonance imaging, and routine cerebrospinal fluid (CSF) findings as those observed in multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, appears to be the most specific CSF marker for MS. This study aimed to determine whether a positive MRZR and other routine CSF markers help differentiate between MS and PCNSL. Data regarding brain biopsy, CSF routine tests, cytopathological examination and immunophenotyping of CSF cells were assessed in 68 PCNSL patients. MRZR was determined, as possible, in PCNSL patients (n = 37) and in those with MS (n = 74; age and sex matched to PSCNL patients) and psychiatric disorders (PD; n = 78). Two stringency levels for a positive antibody index (AI) evaluation (AI ≥ 1.5 and 2.0) were applied, and MRZR was considered positive in cases with ≥ 2 positive AIs (MRZR-2). Using the common AI threshold of ≥ 1.5, MS patients exhibited positive MRZR-2 (58.1%) more frequently than PCNSL (8.1%) and PD patients (2.6%; p < 0.0001 for each comparison with the MS group) corresponding to a positive predictive value (PPV) of 89.6% and a negative predictive value (NPV) of 78.0%. On applying the stricter AI threshold of ≥ 2.0, 37.8% of MS patients were MRZR-2 positive; however, all patients with PCNSL and PD were MRZR-2 negative (p < 0.0001 for each comparison with the MS cohort) resulting in a PPV of 100% and an NPV of 71.4%. Consequently, a positive MRZR-2 result may contribute toward the distinction between MS and PCNSL owing to its high specificity and PPV for MS in the context of the present study. Among the other CSF parameters only a quantitative intrathecal IgG synthesis (present in 49.3% of MS patients but in none of the PCNSL or PD patients; p < 0.0001 for each comparison with the MS group) reliably indicated MS rather than PCNSL.
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http://dx.doi.org/10.1007/s00415-018-8779-xDOI Listing
May 2018

The MRZ reaction helps to distinguish rheumatologic disorders with central nervous involvement from multiple sclerosis.

BMC Neurol 2018 Jan 31;18(1):14. Epub 2018 Jan 31.

Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center - University of Freiburg, Hugstetter Strasse 55, D-79106, Freiburg, Germany.

Background: Some rheumatologic disorders may initially manifest with central nervous system (CNS) affection, mimicking the clinical, magnetic resonance imaging, and cerebrospinal fluid findings of multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, has been found positive frequently in MS patients. However, it is unclear whether the MRZR is helpful to distinguish rheumatologic disorders with CNS involvement (RDwCNS) from MS.

Methods: The MRZR was evaluated in patients with RDwCNS (n = 23), MS (n = 46; age and sex matched to patients with RDwCNS), and other inflammatory autoimmune neurological diseases affecting the CNS (OIND; n = 48). Both the stringency levels that have been used in previous MRZR studies, MRZR-1 (≥ 1 of 3 AIs positive) and MRZR-2 (≥ 2 of 3 AIs positive), were applied.

Results: There was no statistically significant difference in the prevalence of positive MRZR between patients with RDwCNS (MRZR-1: 13.0% and MRZR-2: 8.7%, respectively) and OIND (MRZR-1: 22.9% and MRZR-2: 8.3%, respectively). Compared to these two study cohorts, the MS group exhibited significantly higher prevalences of positive MRZR (MRZR-1: 82.6%, MRZR-2: 63.0%; p < 0.005 each).

Conclusions: Considering the high specificity of MRZR-2 for MS found in this study, MRZR-2 can be a useful diagnostic tool for distinguishing MS from RDwCNS or OIND.
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http://dx.doi.org/10.1186/s12883-018-1018-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793342PMC
January 2018

Do patients with schizophreniform and bipolar disorders show an intrathecal, polyspecific, antiviral immune response? A pilot study.

Fluids Barriers CNS 2017 Dec 7;14(1):34. Epub 2017 Dec 7.

Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: We previously described inflammatory cerebrospinal fluid (CSF) alterations in a subgroup of patients with schizophreniform disorders and the synthesis of polyspecific intrathecal antibodies against different neurotropic infectious pathogens in some patients with bipolar disorders. Consequently, we have measured the prevalence of a positive MRZ reaction (MRZR)-a marker for a polyspecific, antiviral, intrathecal, humoral immune response composed of three antibody indices for the neurotropic viruses of measles (M), rubella (R), and varicella zoster (Z)-in these patients.

Methods: We analyzed paired CSF and serum samples of 39 schizophreniform and 39 bipolar patients. For comparison, we used a group of 48 patients with other inflammatory neurological disorders (OIND) and a cohort of 203 multiple sclerosis (MS) patients.

Results: We found a positive MRZR in two patients with schizophreniform disorders (5.1%); both suffered from schizodepressive disorders without any other signs suggestive of MS. None of the bipolar patients (0%) and four members of the OIND group (8.3%) showed a positive MRZR. In the MS cohort, a positive MRZR was found significantly more frequently [in 99 patients (48.8%)] than in the other patient groups (p > 0.001). In summary, we did not find a positive MRZR in a relevant subgroup of patients with schizophreniform or bipolar disorders.

Conclusions: Our results indicate that the MRZR is highly specific to MS. Nevertheless, two schizodepressive patients also had a positive MRZR. This finding corresponds to the few MRZR-positive patients with OIND or other autoimmune disorders with central nervous involvement, implicating that the MRZR specificity for MS is high, but not 100%.
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http://dx.doi.org/10.1186/s12987-017-0082-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719745PMC
December 2017

Retrospective analysis of clinical and virological parameters of influenza cases at four university hospitals in Germany, 2015.

Infection 2017 Jun 18;45(3):349-354. Epub 2017 Mar 18.

Institute for Virology, Medical Center - University of Freiburg, Hermann-Herder-Str. 11, 79014, Freiburg, Germany.

We conducted a retrospective observational study at four German university hospitals of patients with laboratory-confirmed influenza in 2014/2015. Overall, a fatality rate of 8% was observed. Significantly more A(H1N1)pdm09 patients were admitted to ICU compared to those with A(H3N2). However, fatal outcome was not significantly increased among A(H1N1)pdm09 cases. Nosocomial infections were seen in 17% of cases. Systematic collection of data from hospitals will complement national influenza surveillance.
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http://dx.doi.org/10.1007/s15010-017-1008-1DOI Listing
June 2017

The MRZ reaction in primary progressive multiple sclerosis.

Fluids Barriers CNS 2017 Feb 7;14(1). Epub 2017 Feb 7.

Department of Neurology and Neurophysiology, University Medical Center Freiburg, Breisacher Strasse 64, 79106, Freiburg, Germany.

Background: The MRZ reaction (MRZR), composed of the three antibody indices (AI) against measles, rubella and varicella zoster virus and found positive in the majority of relapsing-remitting multiple sclerosis (RRMS) patients, is absent in other inflammatory neurological diseases (OIND). So far, it has been uncertain whether its differential diagnostic promise extends to patients with primary-progressive multiple sclerosis (PPMS).

Objective: To investigate the prevalence of MRZR in PPMS compared to RRMS and OIND patients.

Methods: MRZR was assessed in patients with PPMS (n = 103), RRMS (n = 100) and OIND (n = 48). Both stringency levels for MRZR testing, MRZR-1 (≥1 AI positive) and MRZR-2 (≥2 AI positive), were applied.

Results: Prevalence of positive MRZR-1 was 83.5% in PPMS and 67.8% in RRMS (p < 0.05). A positive MRZR-2 was found in 54.4% of PPMS and in 43.0% of RRMS patients (not significant). Compared to both MS subgroups, OIND patients exhibit lower frequencies of positive MRZR (MRZR-1: 22.9%, MRZR-2: 8.3%; p < 0.0001 each).

Conclusion: Positive MRZR was at least as frequent in PPMS as in RRMS and much less frequent in OIND, confirming its promise as a potentially useful diagnostic tool for distinguishing both MS course types from OIND.
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http://dx.doi.org/10.1186/s12987-016-0049-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294835PMC
February 2017

High-temperature short-time pasteurisation of human breastmilk is efficient in retaining protein and reducing the bacterial count.

Acta Paediatr 2017 May 28;106(5):763-767. Epub 2017 Feb 28.

Division of Neonatology, Center for Pediatrics, Medical Center - University of Freiburg, Freiburg, Germany.

Aim: Milk banks are advised to use Holder pasteurisation to inactivate the cytomegalovirus, but the process adversely affects the bioactive properties of human breastmilk. This study explored the antibacterial efficacy of an alternative high-temperature short-time (HTST) treatment of human breastmilk and its effect on marker proteins, compared with the Holder method.

Methods: Breastmilk samples were obtained from 27 mothers with infants in a German neonatal intensive care unit. The samples were either heated to 62°C for five seconds using HTST or processed using Holder pasteurisation, at 63 ± 0.5°C for 30 minutes. Immunoglobulin A, lactoferrin, lysozyme, alkaline phosphatase and bile salt-stimulated lipase concentrations and bacterial colony-forming units/mL were measured before and after heating.

Results: HTST-treated samples retained higher rates of immunoglobulin A (95% versus 83%), alkaline phosphatase (6% versus 0%) and bile salt-stimulated lipase (0.8% versus 0.4%) than Holder pasteurisation samples (all p < 0.01), but not lactoferrin (32% versus 20%, p = 0.18) and lysozyme (72% versus 65%, p = 1). No difference in antibacterial efficacy was noted between the two groups (p = 0.29).

Conclusion: Using the HTST treatment protocol retained some of the bioactive properties of human breastmilk and appeared to have similar antibacterial efficacy to Holder pasteurisation.
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http://dx.doi.org/10.1111/apa.13768DOI Listing
May 2017

Multilocular Facial Necrosis in a Young Boy: A Quiz.

Acta Derm Venereol 2017 02;97(2):299-301

Department of Dermatology and Venerology, University Medical Centre, Hauptstraße 7, D-79104 Freiburg, Germany.

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http://dx.doi.org/10.2340/00015555-2499DOI Listing
February 2017

Influenza A virus drift variants reduced the detection sensitivity of a commercial multiplex nucleic acid amplification assay in the season 2014/15.

Arch Virol 2016 Sep 17;161(9):2417-23. Epub 2016 Jun 17.

Institute of Virology, Medical Center - University of Freiburg, Hermann-Herder-Str. 11, 79104, Freiburg, Germany.

The influenza season 2014/15 was dominated by drift variants of influenza A(H3N2), which resulted in a reduced vaccine effectiveness. It was not clear if the performance of commercial nucleic-acid-based amplification (NAT) assays for the detection of influenza was affected. The purpose of this study was to perform a real-life evaluation of two commercial NAT assays. During January-April 2015, we tested a total of 665 samples from patients with influenza-like illness using the Fast Track Diagnostics Respiratory pathogens 21, a commercial multiplex kit, (cohorts 1 and 2, n = 563 patients) and the Xpert Flu/RSV XC assay (cohort 3, n = 102 patients), a single-use cartridge system. An in-house influenza real-time RT-PCR (cohort 1) and the RealStar Influenza RT-PCR 1.0 Kit (cohort 2 and 3) served as reference tests. Compared to the reference assay, an overall agreement of 95.9 % (cohort 1), 95 % (cohort 2), and 98 % (cohort 3) was achieved. A total of 24 false-negative results were observed using the Fast Track Diagnostics Respiratory pathogens 21 kit. No false-negative results occurred using the Xpert Flu/RSV XC assay. The Fast Track Diagnostics Respiratory pathogens 21 kit and the Xpert Flu/RSV XC assay had sensitivities of 90.7 % and 100 % and specificities of 100 % and 94.1 %, respectively, compared to the RealStar 1.0 kit. Upon modification of the Fast Track Diagnostics Respiratory pathogens 21 kit, the sensitivity increased to 97.3 %. Influenza virus strains circulating during the 2014/15 season reduced the detection sensitivity of a commercial NAT assay, and continuous monitoring of test performance is therefore necessary.
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http://dx.doi.org/10.1007/s00705-016-2930-8DOI Listing
September 2016

Assessing Immunity to Rubella Virus: a Plea for Standardization of IgG (Immuno)assays.

J Clin Microbiol 2016 07 4;54(7):1720-1725. Epub 2016 May 4.

AP-HP, Hôpital Paul Brousse, Groupe Hospitalier Universitaire Paris-Sud, Virologie, WHO Rubella NRL, National Reference Laboratory for Maternofetal Rubella Infections, University Paris-Sud, INSERM U1193, Villejuif, France

Immunity to rubella virus (RV) is commonly determined by measuring specific immunoglobulin G (RV IgG). However, RV IgG results and their interpretation may vary, depending on the immunoassay, even though most commercial immunoassays (CIAs) have been calibrated against an international standard and results are reported in international units per milliliter. A panel of 322 sera collected from pregnant women that tested negative or equivocal for RV IgG in a prior test (routine screening) was selected. This panel was tested with two reference tests, immunoblotting (IB) and neutralization (Nt), and with 8 CIAs widely used in Europe. IB and Nt gave concordant results on 267/322 (82.9%) sera. Of these, 85 (26.4%) sera were negative and 182 (56.5%) sera were positive for both tests. All 85 IB/Nt-negative samples were classified as negative with all CIAs. Of the 182 IB/Nt-positive samples, 25.3 to 61.5% were classified as equivocal and 6 to 64.8% were classified as positive with the CIAs. Wide variations in titers in international units per milliliter were observed. In our series, more than half of the women considered susceptible to RV based on CIA results tested positive for RV antibodies by IB/Nt. Our data suggest that (i) sensitivity of CIAs could be increased by considering equivocal results as positive and (ii) the definition of immunity to RV as the 10-IU/ml usual cutoff as well as the use of quantitative results for clinical decisions may warrant reconsideration. A better standardization of CIAs for RV IgG determination is needed.
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http://dx.doi.org/10.1128/JCM.00383-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922105PMC
July 2016

High specificity of a novel Zika virus ELISA in European patients after exposure to different flaviviruses.

Euro Surveill 2016 Apr;21(16)

Institute for Virology, Medical Center - University of Freiburg, Freiburg, Germany.

The current Zika virus (ZIKV) epidemic in the Americas caused an increase in diagnostic requests in European countries. Here we demonstrate high specificity of the Euroimmun anti-ZIKV IgG and IgM ELISA tests using putative cross-reacting sera of European patients with antibodies against tick-borne encephalitis virus, dengue virus, yellow fever virus and hepatitis C virus. This test may aid in counselling European travellers returning from regions where ZIKV is endemic.
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http://dx.doi.org/10.2807/1560-7917.ES.2016.21.16.30203DOI Listing
April 2016

The intrathecal, polyspecific antiviral immune response in neurosarcoidosis, acute disseminated encephalomyelitis and autoimmune encephalitis compared to multiple sclerosis in a tertiary hospital cohort.

Fluids Barriers CNS 2015 Dec 13;12:27. Epub 2015 Dec 13.

Department of Neurology and Neurophysiology, University Medical Center Freiburg, Breisacher Strasse 64, 79106, Freiburg, Germany.

Background: A polyspecific, intrathecal humoral immune response against the neurotropic viruses, measles, rubella and varicella zoster virus, called "MRZ reaction" (MRZR), is present in the majority of patients with multiple sclerosis (MS). Neurosarcoidosis (NS) and acute disseminated encephalomyelitis (ADEM) are important clinical differential diagnoses of MS. Autoimmune encephalitis (AIE) represents a well characterized autoimmune CNS disorder with intrathecal antibody synthesis. The aim of this study was to investigate the specificity of MRZR for MS in patients with NS, ADEM and AIE for the first time, and to compare it with the diagnostic value of oligoclonal bands (OCB).

Patients And Methods: Twenty-two patients with NS, 17 with AIE, 8 with ADEM and 33 with MS serving as controls were analyzed for OCB and MRZR by calculation of the antibody index (AI) for each virus. MRZR was considered as positive if at least two AIs were ≥1.5.

Results: A positive MRZR was statistically significantly less frequent in NS (9%), AIE (11%) and ADEM (0%) compared to MS patients (70%; p < 0.001 each). The specificity of MRZR for MS was 92% in the study cohort. In comparison to MRZR, the OCB showed a higher sensitivity (100%), but a lower specificity (69%) for MS.

Conclusion: These results indicate that MRZR seems to be the most specific available CSF marker of MS.
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http://dx.doi.org/10.1186/s12987-015-0024-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677451PMC
December 2015

Performance of 14 rubella IgG immunoassays on samples with low positive or negative haemagglutination inhibition results.

J Clin Virol 2016 Jan 19;74:13-8. Epub 2015 Nov 19.

Institute of Virology, University Medical Center Freiburg, Germany.

Background: Rubella IgG testing is routinely done in prenatal care and seroepidemiological studies. Recently concern was raised that seropositivity rates were decreasing questioning vaccination policies. Manufacturers of rubella IgG assays and authors of seroepidemiological studies use different cut-offs for the definition of seropositivity. As rubella virus circulation is reduced since many years, seronegativity rates might be overestimated using an inappropriate cut-off.

Objectives: Using different cut-off definitions we compared fourteen current rubella IgG immunoassays for sensitivity and qualitative result concordance in samples with low positive or negative haemagglutination inhibition (HI) titre.

Study Design: 150 clinical samples from patients and health care workers were included in the study. All samples were measured in 14 different rubella IgG immunoassays. Seropositivity was defined using recombinant rubella IgG immunoblot as reference standard.

Results: The concordance of qualitative results using the manufacturers cut-off definitions was 56.4% if grey-zone results were analysed separately and 69.8% if grey-zone results were defined as positive. Using universal cut-offs of 10 IU/ml or 15 IU/ml the concordance was 70% and 61.4% respectively. Using the different cut-off definitions up to 71 out of the 124 immunoblot-positive samples tested negative in the immunoassays. The mean coefficient of variation (CV) of quantitative results in positive samples was 51% (range 19-113%).

Conclusions: Determination of rubella immunity by measurement of rubella-IgG in a population with high vaccination coverage with current assays leads to a high number of false negative results. The value of routine rubella antibody testing in countries with high vaccination coverage should be discussed.
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http://dx.doi.org/10.1016/j.jcv.2015.11.022DOI Listing
January 2016

Characterisation of nosocomial and community-acquired influenza in a large university hospital during two consecutive influenza seasons.

J Clin Virol 2015 Dec 24;73:47-51. Epub 2015 Oct 24.

Institute for Virology, Medical Center-University of Freiburg, Freiburg, Germany. Electronic address:

Background: Nosocomial influenza is increasingly recognized as an important public health threat causing considerable morbidity and mortality each year. However, data on nosocomial influenza is usually collected during outbreaks only and clinical information of nosocomial influenza is sparsely available.

Objectives: To systematically analyse the distribution of nosocomial and community-acquired influenza and epidemiological characteristics in a tertiary care unit in two consecutive seasons.

Study Design: A retrospective observational study was conducted to identify and characterise cases of nosocomial and community-acquired influenza at Freiburg University hospital from 1 January 2013 to 30 April 2014. A validated multiplex RT-PCR to detect influenza virus and other respiratory pathogens was used throughout. Clinical information was retrieved from the hospital-based information system.

Results: Overall, 218 patients with laboratory-confirmed influenza were included (179 in the first, 39 patients in the second season). A rate of 20% of nosocomial influenza was observed throughout. A fatal outcome was recorded for 9% of nosocomial cases, which were mainly associated with influenza virus A(H1N1)pdm09. Nosocomial influenza occurred in all age groups, but fatalities were only observed in patients ≥18 years. Patients with nosocomial influenza were significantly older, underwent therapy for blood malignancies and immunosuppressive regimens more frequently, and received solid organ transplantation more often compared to community-acquired patients.

Conclusions: Despite the different distribution of virus subtypes and epidemiological properties between both influenza seasons, the rate of nosocomial cases remained similar. Systematic detection and targeted prevention measures seem mandatory to minimize nosocomial influenza.
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http://dx.doi.org/10.1016/j.jcv.2015.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185613PMC
December 2015

[Not Available].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2015 Sep;58(9):1025

Nationales Referenzzentrum für Retroviren, Universitätsklinikum Frankfurt, Frankfurt, Deutschland.

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http://dx.doi.org/10.1007/s00103-015-2214-6DOI Listing
September 2015

Importance of molecular typing in confirmation of the source of a national hepatitis A virus outbreak in Norway and the detection of a related cluster in Germany.

Arch Virol 2015 Nov 7;160(11):2823-6. Epub 2015 Aug 7.

Department of Infectious Disease Epidemiology, Norwegian Institute of Public Health, Postboks 4404 Nydalen, NO-0403, Oslo, Norway.

In March 2014, after an increase of notifications of domestically acquired hepatitis A virus infections, an outbreak investigation was launched in Norway. Sequenced-based typing results showed that these cases were associated with a strain that was identical to one causing an ongoing multinational outbreak in Europe linked to frozen mixed berries. Thirty-three confirmed cases with the outbreak strain were notified in Norway from November 2013 to June 2014. Epidemiological evidence and trace-back investigations linked the outbreak to the consumption of a berry mix cake. Identification of the hepatitis A virus outbreak strain in berries from one of the implicated cakes confirmed the cake to be the source. Subsequently, a cluster in Germany linked to the cake was also identified.
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http://dx.doi.org/10.1007/s00705-015-2531-yDOI Listing
November 2015

Analysis of specific IgG titers against tick-borne encephalitis in patients with primary antibody deficiency under immunoglobulin substitution therapy: impact of plasma donor origin.

Front Immunol 2014 5;5:675. Epub 2015 Jan 5.

Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg , Freiburg , Germany.

Immunoglobulin (Ig) replacement therapy is effective in reducing infections in patients with primary antibody deficiency (PAD). Diversity of specific antibodies is achieved by pooling plasma from over 1000 donors usually of a given geographic region. However, there is no agreement with regard to an optimal vaccination schedule for plasma donors. Especially for tick-borne encephalitis (TBE), regional vaccination rates differ widely among populations due to the epidemiology of the disease. We analyzed specific antibody titers against TBE in comparison to total IgG levels in 162 serum samples collected from 110 PAD patients substituted with polyvalent intravenous IgG or subcutaneous IgG. Some patients received different IgG products over time leading to a total number of 122 different patient-IgG product combinations. Positive TBE-specific IgG levels were detected in 35 cases when measured by standard ELISA and could be confirmed by demonstration of neutralizing antibodies in 31 cases. The detection of specific antibody levels correlated with the geographic origin of the IgG preparations. No titers were detectable in patients substituted with IgG products from North-American donors, whereas variable degrees of anti-TBE titers were observed in patients receiving products from different European countries. We suggest considering the patients' personal risk for TBE when selecting an appropriate Ig preparation. These data support regional plasma donation in order to address the diverse local infection profile.
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http://dx.doi.org/10.3389/fimmu.2014.00675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283645PMC
January 2015

A human adenovirus species B subtype 21a associated with severe pneumonia.

J Infect 2014 Nov 27;69(5):490-9. Epub 2014 Jun 27.

Institut für Virologie, Medizinische Hochschule, Hannover, Germany; Netzwerk Atemwegsinfektionen des Robert-Koch-Institutes, Adenovirus Konsiliarlabor, Germany. Electronic address:

Between 2005 and 2013 six severe pneumonia cases (all requiring mechanical ventilation, two fatal outcomes) caused by human adenovirus type 21 (HAdV-B21) were observed in Germany. So far, HAdV-B21 was mainly associated with non-severe upper and lower respiratory tract infections. However, a few highly virulent HAdV types, e.g. HAdV-B14p1, were previously associated with severe, fatal pneumonia. Complete genomic sequences of the German HAdV-B21 pneumonia isolates formed a single phylogenetic cluster with very high sequence identity (≥ 99.897%). Compared to the HAdV-B21 prototype (only 99.319% identity), all isolates had a unique 15 amino acid deletion and a 2 amino acid insertion in the RGD loop of the penton base which may affect binding to the secondary receptor on the host cells. Moreover, a recombinant E4 gene region derived of HAdV-B3 was identified by bootscan analysis. Thus, the highly virulent, pneumotropic HAdV-B21 was denominated as subtype 21a. Surprisingly, there was 99.963% identity with agent Y/SIBU97 (only 13.4 kb available in GenBank of the 35.4 kb genome) which was associated with 10 fatalities due to cardiopulmonary failure in Sarawak, Malaysia, in 1997. In conclusion, a HAdV-B21 subtype (21a) associated with severe pneumonia in Germany was phylogenetically linked to an adenovirus isolated in Malaysia.
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http://dx.doi.org/10.1016/j.jinf.2014.06.015DOI Listing
November 2014

The crucial role of molecular diagnostics.

Dtsch Arztebl Int 2014 Jan;111(1-2):10

*Institut für Virologie, Department für Medizinische Mikrobiologie und Hygiene Universitätsklinikum Freiburg.

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http://dx.doi.org/10.3238/arztebl.2014.0010aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948014PMC
January 2014

Pharmacologically triggered hydrogel for scheduling hepatitis B vaccine administration.

Sci Rep 2013 ;3:2610

1] Faculty of Biology, BIOSS Centre for Biological Signalling Studies, University of Freiburg, Schänzlestrasse 1, 79104 Freiburg, Germany [2] Spemann Graduate School of Biology and Medicine SGBM, University of Freiburg, Albertstrasse 19A, 79104 Freiburg, Germany.

The simplification of current vaccine administration regimes is of crucial interest in order to further sustain and expand the high impact of vaccines for public health. Most vaccines including the vaccine against hepatitis B need several doses to achieve protective immunization. In order to reduce the amount of repetitive injections, depot-based approaches represent a promising strategy. We present the application of novobiocin-sensitive biohybrid hydrogels as a depot for the pharmacologically controlled release of a vaccine against hepatitis B. Upon subcutaneous implantation of the vaccine depot into mice, we were able to release the vaccine by the oral administration of the stimulus molecule novobiocin resulting in successful immunization of the mice. This material-based vaccination regime holds high promises to replace classical vaccine injections conducted by medical personnel by the simple oral uptake of the stimulus thereby solving a major obstacle in increasing hepatitis B vaccination coverage.
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http://dx.doi.org/10.1038/srep02610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767947PMC
June 2014

Acute fibrinous and organizing pneumonia associated with influenza A/H1N1 pneumonia after lung transplantation.

BMC Pulm Med 2013 May 19;13:30. Epub 2013 May 19.

Institute of Pathology, University Medical Center Freiburg, Breisacher Strasse 115a, Freiburg, D-79106, Germany.

Background: Immunocompromised patients, particularly after lung transplantation, are at high risk to develop atypical forms of pulmonary infections including influenza A/H1N1. Acute Fibrinous and Organizing Pneumonia (AFOP) is a special histological pattern in acute respiratory failure with high mortality.

Case Presentation: We describe a 66-year-old woman with double lung transplantation in August 2009 due to end stage pulmonary fibrosis. After prolonged weaning and subsequent promising course, she developed atypical pneumonia with diffuse pulmonary infiltrates in both lungs in January 2010. Infection with influenza A/H1N1 virus was verified. The patient rapidly suffered from respiratory insufficiency and died eight days after this diagnosis. The post-mortem revealed especially in the lower parts of the lungs the classical histological pattern of pure AFOP. Molecular analyses of lung tissue were positive for influenza A/H1N1.

Conclusion: To our knowledge we present the first case of AFOP triggered by viral infection, here proven to be influenza virus A/H1N1. Thus, also in the setting of viral infection the highly deadly differential diagnosis of AFOP must be considered.
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http://dx.doi.org/10.1186/1471-2466-13-30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662564PMC
May 2013

Influenza virus A(H1N1)pdm09 hemagglutinin polymorphism and associated disease in southern Germany during the 2010/11 influenza season.

Arch Virol 2013 Jun 9;158(6):1297-303. Epub 2013 Feb 9.

Department of Virology, Institute for Medical Microbiology and Hygiene, University Medical Center, Hermann-Herder Str. 11, 79104 Freiburg, Germany.

A novel influenza A virus emerged in early 2009 to cause the first influenza pandemic of the 21(st) century. Understanding the evolution of influenza virus is crucial to determine pathogenesis, vaccine efficacy, and resistance to antiviral drugs. In this study, we investigated the molecular evolution of influenza virus A(H1N1)pdm09 in the 2010/11 influenza season in southern Germany by sequence analysis of the influenza virus hemagglutinin gene from 25 patients with mild, moderate, and severe disease. Phylogenetic analysis revealed co-circulation of different genetic groups. The D222G mutation, which had previously been observed in severe cases, was not detected. Immunocompromised patients were not affected more severely than non-immunocompromised patients (p>0.05), although longer shedding was observed in some of them. Interestingly, additional mutations and potential glycosylation sites were detected in samples from the lower respiratory tract in two patients, but not in the corresponding upper respiratory tract specimens. The H275Y mutation in the influenza virus neuraminidase gene, known to confer resistance to the neuraminidase inhibitor oseltamivir, was detected in one patient.
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http://dx.doi.org/10.1007/s00705-013-1610-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087040PMC
June 2013