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Abstract Aims The association of human herpesvirus 6 (HHV-6) species with pancreatic cancer is controversially discussed. The aim of this study was to further investigate the postulated association and to identify the basis of HHV-6 DNA positivity reported for pancreatic cancer tissue. Methods All samples of patients with pancreatic cancer (cancer and surrounding tissue) were analyzed for presence of HHV-6 DNA by PCR and then selected cases by immunohistochemistry. Results Sixty eight per cent (68% = 52/77) of all patients were HHV-6 DNA positive in any of the samples, 49% (38/77) were positive in tumor tissue. Specimens of just one patient were HHV-6A DNA positive, all other patients were positive for HHV-6B. Immunohistochemical analysis of HHV-6 DNA positive samples did not reveal any specific HHV-6B protein positive tumor cell. In contrast, supposed immune cells presented intra- and peritumorally expressed HHV-6B-protein. The cause of presence of these cells in the tumor stroma is unknown, as of yet. Conclusions HHV-6 DNA-positivity of pancreatic cancer tissue described by us and others is probably not due to the infection of pancreatic cells by HHV-6, but rather due to the migration of HHV-6 positive immune cells into the pancreas. Based on our data, we suppose that there is no direct evidence for HHV-6 as a causative agent of pancreatic cancer, but further in-depth studies (including investigation of immune status of patients) are necessary to make definitive conclusions.

Background: Puumala hantavirus (PUUV) causes nephropathia epidemica (NE), an endemic form of transient acute renal injury (AKI). Serological testing is the mainstay of diagnosis. It was the aim of the present study to assist decision-making for serological testing by constructing a simple tool that predicts the likelihood of PUUV positivity., Methods: We conducted a comparative cohort study of all PUUV-tested cases at Aachen University tertiary care center in Germany between mid-2013 and mid-2021. N = 293 qualified for inclusion; N = 30 had a positive test result and clinical NE; N = 263 were negative. Two predictive point scores, the Aachen PUUV Score (APS) 1 and 2, respectively, were derived with the aid of logistic regression and receiver operating characteristic (ROC) analysis by determining the presence of four admission parameters. For internal validation, the internal Monte Carlo method was applied. In addition, partial external validation was performed using an independent historic cohort of N = 41 positive cases of NE., Results: APS1 is recommended for clinical use as it estimated the probability of PUUV positivity in the entire medical population tested. With a range from 0 to 6 points, it yielded an area under the curve of 0.94 by allotting 2 points each for fever or headache and 1 point each for AKI or LDH>300 U/L. A point sum of 0-2 safely predicted negativity for PUUV, as was confirmed in the NE validation cohort., Conclusion: Here, we present a novel, easy-to-use tool to guide the diagnostic management of suspected PUUV infection/NE and to safely avoid unnecessary serological testing, as indicated by point sum class 0-2. Since 67% of the cohort fell into this stratum, half of the testing should be avoidable in the future., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Brockmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: The association of human herpesvirus 6 (HHV-6) species with pancreatic cancer is controversially discussed. The aim of this study was to further investigate the postulated association and to identify the basis of HHV-6 DNA positivity reported for pancreatic cancer tissue., Methods: All samples of patients with pancreatic cancer (cancer and surrounding tissue) were analyzed for presence of HHV-6 DNA by PCR and then selected cases by immunohistochemistry., Results: Sixty eight per cent (68% = 52/77) of all patients were HHV-6 DNA positive in any of the samples, 49% (38/77) were positive in tumor tissue. Specimens of just one patient were HHV-6A DNA positive, all other patients were positive for HHV-6B. Immunohistochemical analysis of HHV-6 DNA positive samples did not reveal any specific HHV-6B protein positive tumor cell. In contrast, supposed immune cells presented intra- and peritumorally expressed HHV-6B-protein. The cause of presence of these cells in the tumor stroma is unknown, as of yet., Conclusions: HHV-6 DNA-positivity of pancreatic cancer tissue described by us and others is probably not due to the infection of pancreatic cells by HHV-6, but rather due to the migration of HHV-6 positive immune cells into the pancreas. Based on our data, we suppose that there is no direct evidence for HHV-6 as a causative agent of pancreatic cancer, but further in-depth studies (including investigation of immune status of patients) are necessary to make definitive conclusions., (© 2023. The Author(s).)

Purpose: Although the fast development of safe and effective messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 has been a success, waning humoral immunity has led to the recommendation of booster immunization. However, knowledge of the humoral immune response to different booster strategies and the association with adverse reactions is limited., Materials and Methods: We investigated adverse reactions and anti-spike protein immunoglobulin G (IgG) concentrations among health care workers who received primary immunization with mRNA-1273 and booster immunization with mRNA-1273 or BNT162b2., Results: Adverse reactions were reported by 85.1% after the first dose, 94.7% after the second dose, 87.5% after a third dose of BNT162b2, and 86.0% after a third dose of mRNA-1273. They lasted for a median of 1.8, 2.0, 2.5, and 1.8 days, respectively; 6.4%, 43.6%, and 21.0% of the participants were unable to work after the first, second, and third vaccination, respectively, which should be considered when scheduling vaccinations among essential workers. Booster immunization induced a 13.75-fold (interquartile range, 9.30-24.47) increase of anti-spike protein IgG concentrations with significantly higher concentrations after homologous compared to heterologous vaccination. We found an association between fever, chills, and arthralgia after the second vaccination and anti-spike protein IgG concentrations indicating a linkage between adverse reactions, inflammation, and humoral immune response., Conclusion: Further investigations should focus on the possible advantages of homologous and heterologous booster vaccinations and their capability of stimulating memory B-cells. Additionally, understanding inflammatory processes induced by mRNA vaccines might help to improve reactogenicity while maintaining immunogenicity and efficacy., Competing Interests: No potential conflict of interest relevant to this article was reported., (© Korean Vaccine Society.)

Background: So far, typical findings for COVID-19 in computed tomography (CT) have been described as bilateral, multifocal ground glass opacities (GGOs) and consolidations, as well as intralobular and interlobular septal thickening. On the contrary, round consolidations with the halo sign are considered uncommon and are typically found in fungal infections, such as invasive pulmonary aspergillosis. The authors recently observed several patients with COVID-19 pneumonia presenting with round, multifocal consolidations accompanied by a halo sign. As this may indicate alterations of CT morphology based on the virus variant, the aim of this study was to investigate this matter in more detail., Methods: 161 CT scans of patients with confirmed SARS-CoV-2 infection (RT-PCR within 2 days of CT) examined between January 2021 and September 15, 2021 were included. Follow-up examinations, patients with invasive ventilation at the time of CT, and patients with insufficient virus typing for variants of concern (VOC) were excluded. CT scans were assessed for vertical and axial distribution of pulmonary patterns, degree of involvement, uni- vs. bilaterality, reticulations, and other common findings. The mean density of representative lesions was assessed in Hounsfield units. Results were compared using Mann-Whitney U-tests, Student's t-rests, descriptive statistics, and Fisher's exact tests., Results: 75 patients did not meet the inclusion criteria. Therefore, 86/161 CT scans of unique patients were analyzed. PCR VOC testing confirmed manifestation of the Delta-VOC SARS-CoV-2 in 22 patients, 39 patients with Alpha-VOC and the remaining 25 patients with Non-VOC SARS-CoV-2 infections. Three patients with the Delta-VOC demonstrated multiple pulmonary masses or nodules with surrounding halo sign, whereas no patients with either Alpha-VOC (p = 0.043) or non-VOC (p = 0.095) demonstrated these findings. All three patients were admitted to normal wards and had no suspicion of a pulmonary co-infection. Patients with Delta-VOC were less likely to have ground glass opacities compared to Alpha-VOC (7/22 or 31.8 % vs. 4/39 or 10.3 %; p < 0.001), whereas a significant difference has not been observed between Delta-VOC and non-VOC (5/25 or 20 %; p = 0.348). The mean representative density of lesions did not show significant differences between the studied cohorts., Conclusion: In this study 3 out of 22 patients (13.6 %) with Delta-VOC presented with bilateral round pulmonary masses or nodules with surrounding halo signs, which has not been established as a notable imaging pattern in COVID-19 pneumonia yet. Compared to the other cohorts, a lesser percentage of patients with Delta-VOC presented with ground glass opacities. Based on these results Delta-VOC might cause a divergence in CT-morphologic phenotype., Key Points: · Until recently, CT-morphologic signs of COVID-19 pneumonia have been presumed to be uncontroversially understood. Yet, recently the authors observed diverging pulmonary alterations in patients infected with Delta-VOC.. · These imaging alterations included round pulmonary masses or nodules with surrounding halo sign.. · These imaging alterations have not yet been established as typical for COVID-19 pneumonia, yet.. · Based on these results, Delta-VOC could impose a divergence of CT-morphologic phenotype.., Citation Format: · Yüksel C, Sähn M, Kleines M et al. Possible Alterations of Imaging Patterns in Computed Tomography for Delta-VOC of SARS-CoV-2 . Fortschr Röntgenstr 2022; 194: 1229 - 1241., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Many epidemiological aspects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemics, particularly those affecting children, are still sparsely elucidated. Data on the first pandemic phase during the year 2020 indicated that children might serve as a virus reservoir. We now analyzed data on more than 530 000 SARS-CoV-2 polymerase chain reaction (PCR) and 12 503 anti-SARS-CoV-2 antibody tests performed in the west of Germany until Week 4 of 2021. We show that children of at least 10 years of age may play a prominent role in the pandemic showing highest PCR-positive rates in the first (Weeks 28-35), second (Weeks 42-48), and third wave (Week 50 of 2020-Week 2 2021) of the second pandemic phase, although the waves were not mainly initiated by children. The waves' kinetics differed even in nearby cities. Low PCR-positive rates were confined to areas of lower population density. PCR-positive rates were higher among middle-aged males compared with women and among very old females compared with males. From Week 25, seroprevalence rates slowly increased to 50%, indicating ongoing virus activity. In conclusion, the SARS-CoV-2 pandemics is characterized by many local but interacting epidemics, initiated and driven by different social groups. Children may not be the main initiators of virus spreading but older children may significantly affect the course of the pandemic. High population density is associated with higher SARS-CoV-2 incidence., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Purpose: Studies on the immune responses to severe acute respiratory syndrome coronavirus 2 vaccines are necessary to evaluate the ongoing vaccination programs by correlating serological response data and clinical effectiveness data. We performed a longitudinal immunological profiling of health care workers vaccinated with mRNA-1273 (Moderna, Cambridge, MA, USA). Half of these vaccinees had experienced a mild coronavirus disease 2019 (COVID-19) infection in the spring of 2020 ("COVID-recovered" cohort), whereas the other half of the vaccinees had no previous COVID-19 infection ("COVID-naive" cohort)., Materials and Methods: Serum was drawn at multiple time points and subjected to assays measuring anti-Spike immunoglobulin G (IgG), avidity of anti-Spike IgG, avidity of anti-receptor binding domain (RBD) IgG, virus neutralizing activity, and interferon-γ release from stimulated lymphocytes., Results: Between both cohorts and within each cohort, we found remarkable inter-individual differences regarding cellular and humoral immune responses to the Moderna mRNA-1273 vaccine., Conclusion: First, our study indicates that the success of mRNA-1273 vaccinations should be verified by serological assays in order to identify "low-responders" to vaccination. Second, the kinetics of anti-S IgG and neutralizing activity correlate well with clinical effectiveness data, thus explaining incipient protection against infection 2 weeks after the first dose of mRNA-1273 in COVID-naive vaccinees. Third, our IgG-avidity data indicate that this incipient protection is mediated by low-avidity anti-RBD IgG and low-avidity anti-S IgG., Competing Interests: No potential conflict of interest relevant to this article was reported., (© Korean Vaccine Society.)

Background: Due to large vaccination efforts with novel vaccines there is an increasing need for laboratory tests assessing successful immunizations with SARS-CoV-2 vaccines. Unfortunately classical neutralization assays are laborious, time-consuming and require an adequate biosafety level laboratory. Recently, convenient ELISA-based surrogate neutralization assays (sVNTs) for determination of neutralizing SARS-CoV-2 antibodies have been developed., Study Design: Our study compares the two novel ELISA-based SARS-CoV-2 surrogate neutralization assays "cPass SARS-CoV-2 Surrogate Virus Neutralization Test Kit" (GenScript Biotech, USA) and the "TECO SARS-CoV-2 Neutralization Antibody Assay" (TECOmedical, Switzerland) using 93 sera drawn from health care workers (HCVs) 2-3 weeks following the second vaccination with mRNA-1273 and 40 control sera from the pre-SARS-CoV-2 era before 2019., Results: We found a sensitivity of 100% and 91,4% and a specificity of 100% and 100% for the GenScript assay and the TECO assay, respectively. Both sVNTs show a high correlation with anti-S IgG. Moreover, both sVNTs correlate well with each other., Conclusions: Surrogate neutralization assays based on the RBD as bait feature a high specificity and sensitivity for identifying humoral neutralizing activity in individuals vaccinated with the spike-based vaccine mRNA-1273. Although these assays appear well-suited for confirming successful vaccinations with spike-based vaccines, additional studies should compare both assays regarding other purposes such as screening COVID-recovered patients or individuals vaccinated with inactivated whole virus vaccines., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Knowledge about mRNA-1273 elicited T-cell response is limited. We investigated adverse reactions and interferon gamma release by specific T-cells among mRNA-1273 vaccinated health care workers. Seven to 13 weeks after complete vaccination low levels of specific T-cells were detected not correlating with antibody response. Severity of symptoms after first and number of symptoms after second immunization were associated with T-cell response. Assessment of T-cell response in addition to antibody response is crucial because even few specific T-cells could add to protection against infection. Investigation of mRNA-1273 induced inflammatory processes might help improve reactogenicity and immunogenicity., Competing Interests: No potential conflict of interest relevant to this article was reported., (© Korean Vaccine Society.)

Current studies focus on cellular and humoral immunity induced by novel SARS-CoV-2 vaccines. Non-responders to vaccinations are not uncommonly encountered in clinical medicine (e.g. in the field of hepatitis B). Whereas vaccine-induced humoral immunity against SARS-CoV-2 is compromised by emerging Variants of Concern (VOCs), cellular immunity against SARS-CoV-2 is emerging as resilient against VOCs. Thus commercially available test kits for diagnostic laboratories designed to evaluate cellular immune responses to SARS-CoV-2 are urgently needed. Here we evaluated the novel QuantiFERON SARS-CoV-2 assay (Qiagen) measuring INF-ɣ release induced by two spike-derived peptide pools (Ag1 and Ag2) in a cohort of health care workers vaccinated with the mRNA-1273 vaccine and confirmed humoral response. Our study indicates the usefulness of this novel assay for routine laboratories to evaluate cellular immunity against SARS-CoV-2 in response to mRNA-1273 vaccination., (Copyright © 2021. Published by Elsevier B.V.)

Juvenile Idiopathic Arthritis (JIA) patients living in areas with high prevalence of tick-borne-encephalitis-virus-(TBEV)-infection are recommended for administration of inactivated TBE-vaccination. However, there are serious concerns regarding protective vaccine-induced immune responses against TBEV in immunocompromised patients. The present study aimed to analyze the humoral and cellular immune response to TBE-vaccination in previously TBE-vaccinated JIA patients compared to healthy controls (HC) including investigation of IgG-anti-TBEV avidity, neutralization capacity, cellular reactivity by IFNgamma-ELISPOT and cytokine secretion assays. Similar IgG-anti-TBEV antibody concentrations, neutralization titers and cellular reactivity were found between JIA and HC. The number and the early timing of booster vaccinations after primary vaccination had the most prominent effect on neutralizing antibodies in JIA and on IgG-anti-TBEV concentrations in both JIA and HC. Administration of booster vaccinations made it more likely for JIA patients to have IgG-anti-TBEV concentrations ≥165 VIEU/ml and avidities >60%. TNF-alpha inhibitors had a positive and MTX administration a negative effect on humoral immune responses. In conclusion, irrespective of having JIA or not, vaccinated children showed similar humoral and cellular immunity against TBEV several years after primary TBE-vaccination. However, in JIA, booster vaccinations mounted a significantly higher humoral immune response than in JIA without boosters. Our results highlight the need for timely administration of boosters particularly in JIA. Although immunosuppressive treatment at vaccinations in diagnosed JIA had a negative effect mainly on TBEV-specific cellular immunity, most JIA patients mounted a favorable humoral immune response which was maintained over time. Thus, successful TBE-vaccination seems highly feasible in JIA patients with immunosuppressive regimens., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Purpose: To determine the performance of radiologists with different levels of expertise regarding the differentiation of COVID-19 from other atypical pneumonias. Chest CT to identify patients suffering from COVID-19 has been reported to be limited by its low specificity for distinguishing COVID-19 from other atypical pneumonias ("COVID-19 mimics"). Meanwhile, the understanding of the morphologic patterns of COVID-19 has improved and they appear to be fairly specific., Materials and Methods: Between 02/2020 and 04/2020, 60 patients with COVID-19 pneumonia underwent chest CT in our department. Cases were matched with a comparable control group of 60 patients of similar age, sex, and comorbidities, who underwent chest CT prior to 01/2020 for atypical pneumonia caused by other pathogens. Included were other viral, fungal, and bacterial pathogens. All 120 cases were blinded to patient history and were reviewed independently by two radiologists and two radiology residents. Readers rated the probability of COVID-19 pneumonia according to the COV-RADS classification system. Results were analyzed using Clopper-Pearson 95 % confidence intervals, Youden's Index for test quality criteria, and Fleiss' kappa statistics., Results: Overall, readers were able to correctly identify the presence of COVID-19 pneumonia in 219/240 (sensitivity: 91 %; 95 %-CI; 86.9 %-94.5 %), and to correctly attribute CT findings to COVID-19 mimics in 159/240 ratings (specificity: 66.3 %; 59.9 %-72.2 %), yielding an overall diagnostic accuracy of 78.8 % (378/480; 74.8 %-82.3 %). Individual reader accuracy ranged from 74.2 % (89/120) to 84.2 % (101/120) and did not correlate significantly with reader expertise. Youden's Index was 0.57. Between-reader agreement was moderate (κ = 0.53)., Conclusion: In this enriched cohort, radiologists were able to distinguish COVID-19 from "COVID-19 mimics" with moderate diagnostic accuracy. Accuracy did not correlate with reader expertise., Key Points: · In a scenario of direct comparison (no negative findings), CT allows the differentiation of COVID-19 from other atypical pneumonias ("COVID mimics") with moderate accuracy.. · Reader expertise did not significantly influence these results.. · Despite similar patterns and distributions of pulmonary findings, radiologists were able to estimate the probability of COVID-19 pneumonia using the COV-RADS classification in a standardized manner in the larger proportion of cases.., Citation Format: · Sähn M, Yüksel C, Keil S et al. Accuracy of Chest CT for Differentiating COVID-19 from COVID-19 Mimics. Fortschr Röntgenstr 2021; 193: 1081 - 1091., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

A novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in China in December 2019, causing an ongoing, rapidly spreading global pandemic. Worldwide, vaccination is now expected to provide containment of the novel virus, resulting in an antibody-mediated immunity. To verify this, serological antibody assays qualitatively as well as quantitatively depicting the amount of generated antibodies are of great importance. Currently available test methods are either laboratory based or do not have the ability to indicate an estimation about the immune response. To overcome this, a novel and rapid serological magnetic immunodetection (MID) point-of-care (PoC) assay was developed, with sensitivity and specificity comparable to laboratory-based DiaSorin Liaison SARS-CoV-2 S1/S2 IgG assay. To specifically enrich human antibodies against SARS-CoV-2 in immunofiltration columns (IFCs) from patient sera, a SARS-CoV-2 S1 antigen was transiently produced in plants, purified and immobilized on the IFC. Then, an IgG-specific secondary antibody could bind to the retained antibodies, which was finally labeled using superparamagnetic nanoparticles. Based on frequency magnetic mixing technology (FMMD), the magnetic particles enriched in IFC were detected using a portable FMMD device. The obtained measurement signal correlates with the amount of SARS-CoV-2-specific antibodies in the sera, which could be demonstrated by titer determination. In this study, a MID-based assay could be developed, giving qualitative as well as semiquantitative results of SARS-CoV-2-specific antibody levels in patient's sera within 21 min of assay time with a sensitivity of 97% and a specificity of 92%, based on the analysis of 170 sera from hospitalized patients that were tested using an Food and Drug Administration (FDA)-certified chemiluminescence assay., Competing Interests: TS was employed by the company Cape Biologix Technologies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pietschmann, Voepel, Voß, Rasche, Schubert, Kleines, Krause, Shaw, Spiegel and Schroeper.)

Knowledge on the mechanisms of viral spread, of time-related changes, and age-specific factors of severe acute respiratory syndrome coronavirus 2 infections is important to develop recommendations aimed at controlling the pandemic. In this context, longitudinal data on proportions of positive results in different age groups are rare. Data on total positive counts and on shares of positive counts deriving from a private (MVZ) and a University (RWTH) laboratory were analyzed retrospectively and compared with public data on total positive counts of the Robert Koch Institute (RKI). Data were covered for Weeks 9-24 of the year 2020 and all patient ages. Total positive counts were lower in children compared to adults. Proportions of children and adults tested positive were 3%-5% and 5%-7%, respectively. RKI and MVZ data showed similar time-related patterns. Patients of 20-60 years of age did account for the initial virus spread (maximum infection rates at Weeks 9-11). Thereafter, infection rates decreased in older patients whereas children did not show a comparable time-related decrease. Pediatric data generated in outpatient settings and hospitals differed markedly which should be considered in further studies. In summary, compared with adults children are less affected by severe acute respiratory syndrome coronavirus 2 infections and are unlikely to account for the initial viral spread. However, children show sustained viral activity and may serve as a viral reservoir., (© 2020 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Abstract: Chronic renal replacement therapy by either a kidney transplant (KTX) or hemodialysis (HD) predisposes patients to an increased risk for adverse outcomes of COVID-19. However, details on this interaction remain incomplete. To provide further characterization, we undertook a retrospective observational cohort analysis of the majority of the hemodialysis and renal transplant population affected by the first regional outbreak of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) in Germany. In a region of 250,000 inhabitants we identified a total of 21 cases with SARS-CoV-2 among 100 KTX and 260 HD patients, that is, 7 KTX with COVID-19, 14 HD with COVID-19, and 3 HD with asymptomatic carrier status. As a first observation, KTX recipients exhibited trends for a higher mortality (43 vs 18%) and a higher proportion of acute respiratory distress syndrome (ARDS) (57 vs 27%) when compared to their HD counterparts. As a novel finding, development of ARDS was significantly associated with the time spent on previous renal replacement therapy (RRT), defined as the composite of dialysis time and time on the transplant (non-ARDS 4.3 vs ARDS 10.6 years, P = .016). Multivariate logistic regression analysis showed an OR of 1.7 per year of RRT. The association remained robust when analysis was confined to KTX patients (5.1 vs 13.2 years, P = .002) or when correlating the time spent on a renal transplant alone (P = .038). Similarly, longer RRT correlated with death vs survival (P = .0002). In conclusion our data suggest renal replacement vintage as a novel risk factor for COVID-19-associated ARDS and death. The findings should be validated by larger cohorts., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

There is an ongoing need for reliable antigen assays for timely and easy detection of individuals with acute SARS-CoV-2 infection. Using 75 swabs from patients previously tested positive by SARS-CoV-2 PCR and 75 swabs from patients previously tested negative by SARS-CoV-2 PCR, we investigated the sensitivity and specificity of the SARS-CoV-2 Rapid Antigen Test (Roche). We determined a specificity of 96 %. The assay's sensitivity with samples with a cycle threshold of < 25, 25 - <30, 30 - <35, and> = 35 was 100 %, 95 %, 44.8 % and 22.2 %, respectively. We conclude that sensitivity and specificity of the antigen assay is inferior to the PCR assay. However, the antigen assay may be a quick and easy to perform alternative for differentiation of individuals contagious for SARS-CoV-2 from non-contagious individuals., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Some patients with Corona Virus Disease 2019 (COVID-19) develop a severe clinical course with acute respiratory distress syndrome (ARDS) and fatal outcome. Clinical manifestations and biomarkers in early stages of disease with relevant predictive impact for outcomes remain largely unexplored. We aimed to identify parameters which are significantly different between subgroups., Design: 125 patients with COVID-19 were analysed. Patients with ARDS (N = 59) or non-ARDS (N = 66) were compared, as well as fatal outcome versus survival in the two groups., Key Results: ARDS and non-ARDS patients did not differ with respect to comorbidities or medication on developing a fatal outcome versus survival. Body mass index was higher in patients with ARDS versus non-ARDS (p = 0.01), but not different within the groups in survivors versus non-survivors. Interleukin-6 levels on admission were higher in patients with ARDS compared to non-ARDS as well as in patients with fatal outcome versus survivors, whereas lymphocyte levels were lower in the different subgroups (all p<0.05). There was a highly significant 3.5-fold difference in fever load in non-survivors compared to survivors (p<0.0001). Extrapulmonary viral spread was detected more often in patients with fatal outcome compared to survivors (P = 0.01). Further the detection of SARS-CoV-2 in serum showed a significantly more severe course and an increased risk of death (both p<0.05)., Conclusions: We have identified early risk markers for a severe clinical course, like ARDS or fatal outcome. This data might help develop a strategy to address new therapeutic options early in patients with COVID-19 and at high risk for fatal outcome., Competing Interests: The authors have declared that no competing interests exist.

There is an ongoing need for highly reliable serological assays to detect individuals with past SARS-CoV-2 infection. Using 75 sera from patients tested positive or negative by SARS-CoV-2 PCR, we investigated the sensitivity and specificity of the Liaison SARS-CoV-2 S1/S2 IgG assay (DiaSorin), the Elecsys Anti-SARS-CoV-2 assay (Roche), and the ID Screen SARS-CoV-2-N IgG indirect kit (IDVet). We determined a sensitivity of 95.5 %, 95.5 %, and 100 % and a specificity of 90.5 %, 96.2 %, and 92.5 % for the DiaSorin assay, the Roche assay, and the IDVet assay, respectively. We conclude that serologic assays combining very high sensitivity and specificity are still not commercially available for SARS-CoV-2. For maximizing sensitivity and specificity of SARS-CoV-2 serological diagnostics, the combination of two assays may be helpful., (Copyright © 2020 Elsevier B.V. All rights reserved.)

COVID-19 carries a high risk of severe disease course, particularly in patients with comorbidities. Therapy of severe COVID-19 infection has relied on supportive intensive care measures. More specific approaches including drugs that limit the detrimental "cytokine storm", such as Janus-activated kinase (JAK) inhibitors, are being discussed. Here, we report a compelling case of a 55-yo patient with proven COVID-19 pneumonia, who was taking the JAK1/2 inhibitor ruxolitinib in-label for co-existing primary myelofibrosis for 15 months prior to coronavirus infection. The patient had significant comorbidities, including chronic kidney disease, arterial hypertension, and obesity, and our previous cohort suggested that he was thus at high risk for acute respiratory distress syndrome (ARDS) and death from COVID-19. Since abrupt discontinuation of ruxolitinib may cause fatal cytokine storm and ARDS, ruxolitinib treatment was continued and was well tolerated, and the patient´s condition remained stable, without the need for mechanical ventilation or vasopressors. The patient became negative for SARS-CoV-2 and was discharged home after 15 days. In conclusion, our report provides clinical evidence that ruxolitinib treatment is feasible and can be beneficial in patients with COVID-19 pneumonia, preventing cytokine storm and ARDS., (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Facing the ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an urgent need for serological assays identifying individuals with past coronavirus disease 2019 (COVID-19)., Study Design: Our study is the first to compare four new commercially available assays using 75 sera from patients tested positive or negative by SARS-CoV-2 PCR: the anti SARS-CoV-2 ELISA (IgG) (Euroimmun, Germany), the EDI New Coronavirus COVID-19 IgG ELISA, (Epitope diagnostics (EDI), USA), the recomWell SARS-CoV-2 IgG ELISA (Mikrogen, Germany), and the SARS-CoV-2 Virachip IgG (Viramed, Germany)., Results: We found a sensitivity of 86.4 %, 100 %, 86.4 %, and 77.3 % and a specificity of 96,2 %, 88,7 %, 100 %, and 100 % for the Euroimmun assay, the EDI assay, the Mikrogen assay, and the Viramed assay, respectively., Conclusions: Commercially available SARS-CoV-2 IgG assays have a sufficient specificity and sensitivity for identifying individuals with past SARS-CoV-2 infection., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Only limited evidence has been available to date on the accuracy of systematic low-dose chest computed tomography (LDCT) use in the diagnosis of COVID-19 in patients with non-specific clinical symptoms., Methods: The COVID-19 Imaging Registry Study Aachen (COVID-19-Bildgebungs-Register Aachen, COBRA) collects data on imaging in patients with COVID-19. Two of the COBRA partner hospitals (RWTH Aachen University Hospital and Dueren Hospital) systematically perform reverse transcriptase polymerase chain reaction (RT-PCR) from nasopharyngeal swabs as well as LDCT in all patients presenting with manifestations that are compatible with COVID-19. In accordance with the COV-RADS protocol, the LDCT scans were prospectively evaluated before the RT-PCR findings were available in order to categorize the likelihood of COVID-19., Results: From 18 March to 5 May 2020, 191 patients with COVID-19 manifestations (117 male, age 65 ± 16 years) underwent RT-PCR testing and LDCT. The mean time from the submission of the sample to the availability of the RT-PCR findings was 491 minutes (interquartile range [IQR: 276-1066]), while that from the performance of the CT to the availability of its findings was 9 minutes (IQR: 6-11). A diagnosis of COVID-19 was made in 75/191 patients (39%). The LDCT was positive in 71 of these 75 patients and negative in 106 of the 116 patients without COVID-19, corresponding to 94.7% sensitivity (95% confidence interval [86.9; 98.5]), 91.4% specificity [84.7; 95.8], positive and negative predictive values of 87.7% [78.5; 93.9] and 96.4% [91.1; 98.6], respectively, and an AUC (area under the curve) of 0.959 [0.930; 0.988]. The initial RT-PCR test results were falsely negative in six patients, yielding a sensitivity of 92.0% [83.4; 97.0]; these six patients had positive LDCT findings. 47.4% of the LDCTs that were negative for COVID-19 (55/116) exhibited pathological pulmonary changes, including infiltrates, that were correctly distinguished from SARS-CoV-2 related changes., Conclusion: In patients with symptoms compatible with COVID-19, LDCT can esablish the diagnosis of COVID-19 with comparable sensitivity to RT-PCR testing. In addition, it offers a high specificity for distinguishing COVID-19 from other diseases associated with the same or similar clinical symptoms. We propose the systematic use of LDCT in addition to RT-PCR testing because it helps correct false-negative RT-PCR results, because its results are available much faster than those of RT-PCRtesting, and because it provides additional diagnostic information useful for treatment planning regardless of the type of the infectious agent.

Background: The type of pneumonia (coronavirus disease 2019, COVID-19) that is caused by the new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) is now spreading across the world in a pandemic. Many patients with COVID-19 were admitted to the University Hospital Aachen during an outbreak that first struck the Heinsberg district in February 2020., Methods: A comparative presentation of the clinical features of the first 50 COVID-19 patients with and without acute respiratory distress syndrome (ARDS) who were hospitalized in the University Hospital Aachen., Results: 24 intubated patients were treated in the intensive care unit for ARDS of varying degrees of severity, while 26 patients who were breathing spontaneously without ARDS, but nevertheless needed supplemental oxygen, were treated in a separate isolation ward. The median age of the patients was 65 (IQR 58-76). The median latency from symptom onset to hospitalization was four days (IQR 1-8). Patients with ARDS had preexisting respiratory diseases more commonly than patients without ARDS (58% [95% confidence interval: 39; 76] versus 42% [26; 61]) and were more commonly overweight or obese (83% [64; 93] versus 42% [26; 61]). The two groups did not differ in viral burden but displayed significant differences in laboratory findings: ARDS patients had persistently elevated values for leukocytes, interleukin-6, lactate dehydrogenase, creatine kinase, and D-dimers over the period of observation. Patients without ARDS had persistently elevated inflammatory parameters and fever for at least one week, with an accompanying need for supplemental oxygen. Three of the patients with ARDS died of multiorgan failure, while four in the non-ARDS group died of respiratory insufficiency., Conclusion: This initial description of a cohort of COVID-19 patients with and without ARDS in Germany reveals that those with ARDS more commonly have preexisting respiratory diseases and obesity, as well as persistently elevated inflammatory markers. COVID-19 patients without ARDS may likewise require prolonged hospitalization because of persistently elevated inflammatory values with a simultaneous need for supplemental oxygen.

To the best of our knowledge, here, we describe the first hospital-wide outbreak of SARS-CoV-2 that occurred in Germany in April 2020. We aim to share our experience in order to facilitate the management of nosocomial COVID-19 outbreaks in healthcare facilities. All patients and hospital workers were screened for SARS-CoV-2 repeatedly. An infection control team on the side was installed. Strict spatial separation of patients and intensified hygiene training of healthcare workers (HCW) were initiated. By the time of reporting, 26 patients and 21 hospital workers were infected with a cluster of cases in the geriatric department. Fourteen patients developed COVID-19 consistent symptoms and five patients with severe pre-existing medical conditions died. The outbreak was successfully contained after intensified infection control measures were implemented and no further cases among patients were detected over a period of 14 days. Strict application of standard infection control measures proved to be successful in the management of nosocomial SARS-CoV-2 outbreaks., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

Background: Rotavirus (RV)-associated infections account for high numbers of hospitalizations in neonates and young infants. Universal mass vaccination (UMV) has been shown to prevent the burden of disease in vaccinated children., Methods: The present study investigated the long-term effects of UMV on RV-associated hospitalizations in children with particular focus on neonates and young infants (≤42 days old) not eligible for vaccination. Ten years of Austrian surveillance data were compared, including 10 960 laboratory-confirmed RV cases before (prevaccination period [PreVP]) and after (postvaccination period [PostVP]) introduction of UMV., Results: A postvaccination decrease in hospitalized community-acquired RV infections by 89.3% was seen in all age groups, including unvaccinated neonates and young infants. Of the latter, 27.6% had a nosocomial RV infection in PreVP, and 19.3% in PostVP. Overall, the proportion of nosocomial RV infections increased from 5.5% in PreVP to 13.0% in PostVP. Breakthrough infections, usually after incomplete RV vaccination, could be identified in 6.2% of patients., Conclusions: Unvaccinated neonates and infants ≤42 days old may indirectly benefit from UMV by reduction of RV infections. Breakthrough infections underline the importance of early and complete protection by the vaccine. In older patients, heightened awareness of nosocomial RV infections is warranted. Identification of RV reservoirs is also needed., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

The cerebrospinal fluid (CSF) polymerase chain reaction (PCR) is the gold standard to detect cerebral viral activity. As positive findings do not prove an impact on the neurological disorder, data interpretation is difficult. To better assess the impact of positive CSF PCR findings in different neurological diseases and to identify coherences facilitating CSF PCR data interpretation, we performed this retrospective analysis of CSF PCR data of 481 pediatric and 2604 adult patients, including herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), and enteroviruses (EV). Nucleic acid of EBV was detected in 1.6% (39/2449), of VZV in 1.3% (34/2624), of HSV in 1.24% (37/2994), of EV in 0.4% (10/2364), of HHV-6 in 0.17% (4/2417), and of CMV in 0.2% (5/2514) of the patients. Newborns and elderly people showed highest infection rates. HSV, VZV, and EV prevailed in typical infectious central nervous system (CNS) diseases; EBV, in further inflammatory neurological diseases; HSV and EBV, in immunocompromised patients; and EBV, HSV, and HHV-6, in further non-inflammatory neurological diseases. Analysis of successive PCR studies revealed delayed viral detection for EBV (6/147) and HSV (1/217), respectively. Rapid viral clearance was typical for HSV, VZV, CMV, and EV infections, although the maximum duration of viral detection was 15days for HSV and 12days for VZV, respectively. This suggests that the detection of HSV, VZV, CMV, and EV strongly indicates symptomatic viral CNS disease. Secondary viral reactivation mostly underlies positive EBV and HHV-6 findings. Their detection does not rule out clinical impact but recommends searching for additional underlying conditions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Herpes simplex virus type 1 (HSV-1), human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) have been suspected to play a causal role in periodontitis pathogenesis. The aim of this study was to determine the prevalence of these viruses in subgingival plaque samples of Caucasian patients with generalized aggressive periodontitis compared to periodontally healthy controls., Methods: A total of 65 patients with aggressive periodontitis and 65 unmatched controls from Germany were investigated in the study. Subgingival plaque samples were analysed for the presence of HSV-1, EBV and HCMV by quantitative real-time polymerase chain reaction assays. Viral antibody titres were determined quantitatively by immunosorbent assays., Results: DNA of HSV-1 and HCMV were detected in 1.5% of the patients and controls, whereas EBV DNA was present in 10.8% and 13.9% respectively. Detection rates of serum IgG against HSV-1 (76.1% versus 73.9%), EBV (98.5% versus 96.9%), HCMV (47.7% versus 46.2%) and IgM levels against HSV-1 (6.2% versus 1.5%), EBV (0% versus 0%), HCMV (0% versus 1.5%) did not significantly differ between patients and controls., Conclusion: The data of our study do not suggest any contribution of HSV-1, EBV or HCMV to aggressive periodontitis in a German population. Ethnic and methodological aspects might have caused conflicting results of previous studies., (© 2012 John Wiley & Sons A/S.)

After field dressing a rabbit in the state of Upper Austria, Austria two members of a family were infected with tularemia in November 2010. The patients were a man in his forties and his father-in-law in his sixties. Tularemia is a rare disease in Austria. In the last 10 years between 2 and 8 cases have been reported annually. Of the total of 40 cases none was reported in the state of Upper Austria. Thus, this case report documents the reemergence of tularemia in Upper Austria.

Human metapneumovirus causes respiratory diseases with outcomes that can be severe in children, the immunocompromised, and the elderly. Synthetic small interfering RNAs (siRNAs) that silence targeted genes can be used as therapeutic agents. Currently, there is no specific therapy for hMPV. In this study, we designed Dicer-substrate siRNAs (DsiRNAs) that target metapneumovirus sequences on the mRNAs of the N, P, and L genes. In vitro, six DsiRNAs were shown to inhibit virus replication using cell proliferation tests. Of those, the DsiRNA that targets the most conserved mRNA sequence was then resynthesized in Evader™ format with heavy 2'-O-methyl modification of the guide strand. In a murine model, the prophylactic administration of this Evader™ DsiRNA was effective at partially inhibiting viral replication of hMPV (13×10(3) vs. 29×10(3)PFU/g of lung; p<0.01), which was not the case for the control, a mismatched DsiRNA. Inhibition was achieved without inducing cytokines or off-target effects. Moreover, the specificity of the siRNA mechanism of action was demonstrated in vitro and in vivo using 5'-RACE methodology. This in vivo approach of using a DsiRNA against hMPV is an important step in the development of synthetic siRNA as a therapeutic agent for this virus., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Viruses of different families encode for regulators of the complement system (RCAs) or acquire such RCAs from the host to get protection against complement-mediated lysis (CML). As hepatitis C virus (HCV) shares no genetic similarity to any known RCA and is detectable at high titers in sera of infected individuals, we investigated whether HCV has adapted host-derived RCAs to resist CML. Here we report that HCV selectively incorporates CD59 while neither CD55, nor CD46 are associated with the virus. The presence of CD59 was shown by capture assays using patient- and cell culture-derived HCV isolates. Association of CD59 with HCV was further confirmed by Western blot analysis using purified viral supernatants from infected Huh 7.5 cells. HCV captured by antibodies specific for CD59 remained infectious for Huh 7.5 cells. In addition, blocking of CD59 in the presence of active complement reduced the titer of HCV most likely due to CML. HCV produced in CD59 knock-down cells were more significantly susceptible to CML compared to wild type virus, but neither replication, assembly nor infectivity of the virus seemed to be impaired in the absence of CD59. In summary our data indicate that HCV incorporates selectively CD59 in its envelope to gain resistance to CML in serum of infected individuals.

The purpose of this study was to delineate the spectrum of neurological diseases attributed to Epstein-Barr virus (EBV) activity. The approach was a retrospective study on patients with EBV activity proven by a positive EBV antibody-specific index (AI) and/or cerebrospinal fluid (CSF) PCR. One hundred six children and adults (AI positive = 77, AI + PCR positive = 3, PCR positive = 26) were identified, most with reactivated infections. Twenty-eight showed typical EBV-related diseases (encephalitis, neuritis, meningitis), 19 further infections (HSV encephalitis, neuroborreliosis, HIV infection, bacterial meningitis), nine immune-mediated disorders (multiple sclerosis, optic neuritis), and 50 further diseases not typical for EBV. The highest AI values occurred in patients with encephalitis. No relationship between disease category or AI values and viral loads was found. Additional reanalysis of 1,500 consecutive CSF EBV PCR studies revealed the highest positive rates among patients with further infections (n = 18/227, 7.9%) but lower rates among patients with typical EBV-related disorders (5/395; 1.3%), immune-mediated disorders (n = 2/174; 1.1%) and other conditions (n = 4/704; 0.6%). Intrathecal EBV activity is not restricted to typical EBV-related disorders, unexpectedly frequent in further CNS infections and also present in non-inflammatory conditions. Prospective studies should assess the pathogenic role of EBV in these different diseases.

Human TLR1 plays an important role in host defense against Mycobacterium tuberculosis. Our aim was to analyze the association of the loss of TLR1 surface expression and TLR1 SNPs with susceptibility to TB. TLR1neg and TLR1pos cells from healthy individuals were identified by flow cytometry and compared by sequencing. TLR1 expression was measured using quantitative real-time PCR and immunoblotting. TLR1 SNP analyses of healthy individuals and TB patients from EU-C and Ghana were performed, and association of the TLR1 genotypes with increased risk of developing TB was statistically evaluated. Lack of TLR1 surface expression accompanied by impaired function was strongly associated with TLR1 SNP G743A. Genotyping of EU-C controls and TB patients revealed an association of TLR1 743A/1805G alleles [OR 2.37 (95% CI 1.13, 4.93), P=0.0219; OR 2.74 (95% CI 1.26, 6.05), P=0.0059] as well as TLR1neg 743AA/1805GG versus TLR1pos genotypes 743AG/1805TG [OR 4.98 (95% CI 1.64, 15.15), P=0.0034; OR 5.70 (95% CI 1.69, 20.35), P=0.0015] and 743AG + GG/1805TG + TT [OR 3.54 (95% CI 1.29, 9.90), P=0.0086; OR 4.17 (95% CI 1.52, 11.67), P=0.0025] with increased susceptibility to TB. No association of G743A with TB was found in Ghana as a result of a low frequency of genotype 743AA. Our data gain new insights in the role of TLR1 in M. tuberculosis defense and provide the first evidence that TLR1 variants are associated with susceptibility to TB in a low-incidence country.

Hepatitis E virus (HEV) is well-known to cause endemic outbreaks of hepatitis in tropical countries, mostly caused by HEV genotypes 1 or 2 and transmitted from humans to humans via the fecal-oral route. In contrast, HEV genotypes 3 or 4 are commonly encountered as sporadic cases in a non-endemic setting; these autochthonous cases are transmitted from animals to humans and commonly affect elderly male subjects. We report a five-month-old caucasian girl presenting with diarrhea, emesis, and elevated ALT. Surprisingly, acute infection with Hepatitis E virus (HEV) genotype 3 was laboratory-confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) and sequencing. Thirteen months later, RT-PCR for HEV from stool tested negative whereas anti-HEV IgG in serum tested positive. Neither HEV RNA nor anti-HEV antibodies could be detected in stool or serum of the parents. To our knowledge, this is the first pediatric case of a HEV infection in Germany. Thus, HEV should be included into the differential diagnosis of pediatric infectious liver and bowel disease., (Copyright © 2010 Elsevier B.V. All rights reserved.)