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Research into the molecular basis of disease trajectory and Long-COVID is important to get insights toward underlying pathophysiological processes. The objective of this study was to investigate inflammation-mediated changes of metabolism in patients with acute COVID-19 infection and throughout a one-year follow up period. The study enrolled 34 patients with moderate to severe COVID-19 infection admitted to the University Clinic of Innsbruck in early 2020. The dynamics of multiple laboratory parameters (including inflammatory markers [C-reactive protein (CRP), interleukin-6 (IL-6), neopterin] as well as amino acids [tryptophan (Trp), phenylalanine (Phe) and tyrosine (Tyr)], and parameters of iron and vitamin B metabolism) was related to disease severity and patients' physical performance. Also, symptom load during acute illness and at approximately 60 days (FU1), and one year after symptom onset (FU2) were monitored and related with changes of the investigated laboratory parameters: During acute infection many investigated laboratory parameters were elevated (e.g., inflammatory markers, ferritin, kynurenine, phenylalanine) and enhanced tryptophan catabolism and phenylalanine accumulation were found. At FU2 nearly all laboratory markers had declined back to reference ranges. However, kynurenine/tryptophan ratio (Kyn/Trp) and the phenylalanine/tyrosine ratio (Phe/Tyr) were still exceeding the 95th percentile of healthy controls in about two thirds of our cohort at FU2. Lower tryptophan concentrations were associated with B vitamin availability (during acute infection and at FU1), patients with lower vitamin B12 levels at FU1 had a prolonged and more severe impairment of their physical functioning ability. Patients who had fully recovered (ECOG 0) presented with higher concentrations of iron parameters (ferritin, hepcidin, transferrin) and amino acids (phenylalanine, tyrosine) at FU2 compared to patients with restricted ability to work. Persistent symptoms at FU2 were tendentially associated with IFN-γ related parameters. Women were affected by long-term symptoms more frequently. Conclusively, inflammation-mediated biochemical changes appear to be related to symptoms of patients with acute and Long Covid., (© 2024. The Author(s).)

Omicron variants are still the dominant SARS-CoV-2 viruses worldwide, therefore determination of the level of protection from infection and severe disease is essential. Here, we investigated humoral and cellular immunity of individuals immunized by ChAdOx1, BNT162b2, and mRNA-1273 and our results show that IgG and neutralization titers wane over time. However, strongest neutralization against Omicron BA.1 and T-cell responses were detected in ChAdOx1 vaccinees 6 months after the second dose, while no long-lasting neutralization was shown against BA.2 in any cohort. Crucially, our investigation revealed that immunity against variants of concern is heterogenic and dependent on the immunization status., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Few studies have directly compared virus-specific antibodies and their neutralizing capacity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild type (WT) and circulating variants of concern despite the reported high efficacy of messenger RNA (mRNA)- and vector-based vaccines., Objective: We assessed SARS-CoV-2 spike protein region 1 (S1)-specific antibodies of BNT162b2, mRNA-1273, and ChAdOx1 vaccinated as well as convalescent coronavirus disease 2019 (COVID-19) patients. We also determined the neutralization ability against SARS-CoV-2 WT and B.1.1.7 (Alpha), B1.1.7 E484K (Alpha-E484K), B.1.351 (Beta), and B.1.617.2 (Delta) variants., Methods: Serum samples of 107 fully vaccinated or convalescent individuals were analyzed for anti-SARS-CoV-2-S1 IgG and IgA as well as for total anti-SARS-CoV-2 receptor binding domain Ig. Furthermore, neutralization capacity as 50% and 90% neutralization titer values against SARS-CoV-2 WT virus and circulating variants were determined., Results: We observed a robust IgG response in all participants; however, the highest titers were detected in mRNA-based vaccine recipients. In case of serum IgA responses, the difference between mRNA- and vector-based vaccines or convalescent patients was even more pronounced. Interestingly, all 3 vaccines could neutralize all tested variants of concern in addition to WT virus, but in some individuals, only low or no neutralization, especially against Alpha-E484K and the Delta variant, was detected., Conclusion: Our study of the efficacy of various COVID-19 vaccines found that mRNA-1273 had the highest neutralization abilities compared to BNT162b2 and ChAdOx1. COVID-19 convalescent patients demonstrated the most heterogeneous range of antibody titers and neutralization abilities, making it hard to assess protection. Furthermore, a significant positive relation between antibodies and the 50% neutralization titer values for immunized and convalescent individuals was determined., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To develop and validate a prognostic model for in-hospital mortality after four days based on age, fever at admission and five haematological parameters routinely measured in hospitalized Covid-19 patients during the first four days after admission., Methods: Haematological parameters measured during the first 4 days after admission were subjected to a linear mixed model to obtain patient-specific intercepts and slopes for each parameter. A prediction model was built using logistic regression with variable selection and shrinkage factor estimation supported by bootstrapping. Model development was based on 481 survivors and 97 non-survivors, hospitalized before the occurrence of mutations. Internal validation was done by 10-fold cross-validation. The model was temporally-externally validated in 299 survivors and 42 non-survivors hospitalized when the Alpha variant (B.1.1.7) was prevalent., Results: The final model included age, fever on admission as well as the slope or intercept of lactate dehydrogenase, platelet count, C-reactive protein, and creatinine. Tenfold cross validation resulted in a mean area under the receiver operating characteristic curve (AUROC) of 0.92, a mean calibration slope of 1.0023 and a Brier score of 0.076. At temporal-external validation, application of the previously developed model showed an AUROC of 0.88, a calibration slope of 0.95 and a Brier score of 0.073. Regarding the relative importance of the variables, the (apparent) variation in mortality explained by the six variables deduced from the haematological parameters measured during the first four days is higher (explained variation 0.295) than that of age (0.210)., Conclusions: The presented model requires only variables routinely acquired in hospitals, which allows immediate and wide-spread use as a decision support for earlier discharge of low-risk patients to reduce the burden on the health care system., Clinical Trial Registration: Austrian Coronavirus Adaptive Clinical Trial (ACOVACT); ClinicalTrials.gov, identifier NCT04351724., Competing Interests: The 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 © 2022 Heber, Pereyra, Schrottmaier, Kammerer, Santol, Rumpf, Pawelka, Hanna, Scholz, Liu, Hell, Heiplik, Lickefett, Havervall, Traugott, Neuböck, Schörgenhofer, Seitz, Firbas, Karolyi, Weiss, Jilma, Thålin, Bellmann-Weiler, Salzer, Szepannek, Fischer, Zoufaly, Gleiss and Assinger.)

Background: SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19., Methods: ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUC SOFA ), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596., Findings: Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUC SOFA (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group., Interpretation: Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options., Funding: Austrian Science Fund and German Center for Cardiovascular Research., Competing Interests: Declaration of interests AB received research funding from Pfizer and Medtronic as well as speaker honoraria from Bayer, Boehringer Ingelheim, Edwards, Medtronic and Novartis. KDR received a research grant from Daiichi-Sankyo Europe GmbH. UM received fees for participation in a data and safety monitoring board from Thermosome. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

T cells play a fundamental role in the early control and clearance of many viral infections of the respiratory system. In SARS-CoV-2-infected individuals, lymphopenia with drastically reduced CD4 + and CD8 + T cells correlates with Coronavirus disease 2019 (COVID-19)-associated disease severity and mortality. In this study, we characterized cellular and humoral immune responses induced in patients with mild, severe and critical COVID-19. Peripheral blood mononuclear cells of 37 patients with mild, severe and critical COVID-19 and 10 healthy individuals were analyzed by IFNγ ELISpot and multi-color flow cytometry upon stimulation with peptide pools covering complete immunodominant SARS-CoV-2 matrix, nucleocapsid and spike proteins. In addition SARS-CoV-2 antibody levels, neutralization abilities and anaphylatoxin levels were evaluated by various commercially available ELISA platforms. Our data clearly demonstrates a significantly stronger induction of SARS-CoV-2 specific CD8 + T lymphocytes and higher IFNγ production in patients with mild compared to patients with severe or critical COVID-19. In all patients SARS-CoV-2-specific antibodies with similar neutralizing activity were detected, but highest titers of total IgGs were observed in critical patients. Finally, elevated anaphylatoxin C3a and C5a levels were identified in severe and critical COVID-19 patients probably caused by aberrant immune complex formation due to elevated antibody titers in these patients. Crucially, we provide a full picture of cellular and humoral immune responses of COVID-19 patients and prove that robust polyfunctional CD8 + T cell responses concomitant with low anaphylatoxin levels correlate with mild infections. In addition, our data indicates that high SARS-CoV-2 antibody titers are associated with severe disease progression., Competing Interests: The 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 Lafon, Diem, Witting, Zaderer, Bellmann-Weiler, Reindl, Bauer, Griesmacher, Fux, Hoermann, Miller, Zabernigg, Wöll, Wilflingseder, Lass-Flörl and Posch.)

Background: Excessive inflammation triggered by a hitherto undescribed mechanism is a hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and is associated with enhanced pathogenicity and mortality., Objective: Complement hyperactivation promotes lung injury and was observed in patients suffering from Middle East respiratory syndrome-related coronavirus, SARS-CoV-1, and SARS-CoV-2 infections. Therefore, we investigated the very first interactions of primary human airway epithelial cells on exposure to SARS-CoV-2 in terms of complement component 3 (C3)-mediated effects., Methods: For this, we used highly differentiated primary human 3-dimensional tissue models infected with SARS-CoV-2 patient isolates. On infection, viral load, viral infectivity, intracellular complement activation, inflammatory mechanisms, and tissue destruction were analyzed by real-time RT-PCR, high content screening, plaque assays, luminex analyses, and transepithelial electrical resistance measurements., Results: Here, we show that primary normal human bronchial and small airway epithelial cells respond to SARS-CoV-2 infection by an inflated local C3 mobilization. SARS-CoV-2 infection resulted in exaggerated intracellular complement activation and destruction of the epithelial integrity in monolayer cultures of primary human airway cells and highly differentiated, pseudostratified, mucus-producing, ciliated respiratory tissue models. SARS-CoV-2-infected 3-dimensional cultures secreted significantly higher levels of C3a and the proinflammatory cytokines IL-6, monocyte chemoattractant protein 1, IL-1α, and RANTES., Conclusions: Crucially, we illustrate here for the first time that targeting the anaphylotoxin receptors C3a receptor and C5a receptor in nonimmune respiratory cells can prevent intrinsic lung inflammation and tissue damage. This opens up the exciting possibility in the treatment of COVID-19., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Antibody tests are essential tools to investigate humoral immunity following SARS-CoV-2 infection or vaccination. While first-generation antibody tests have primarily provided qualitative results, accurate seroprevalence studies and tracking of antibody levels over time require highly specific, sensitive and quantitative test setups., Methods: We have developed two quantitative, easy-to-implement SARS-CoV-2 antibody tests, based on the spike receptor binding domain and the nucleocapsid protein. Comprehensive evaluation of antigens from several biotechnological platforms enabled the identification of superior antigen designs for reliable serodiagnostic. Cut-off modelling based on unprecedented large and heterogeneous multicentric validation cohorts allowed us to define optimal thresholds for the tests' broad applications in different aspects of clinical use, such as seroprevalence studies and convalescent plasma donor qualification., Findings: Both developed serotests individually performed similarly-well as fully-automated CE-marked test systems. Our described sensitivity-improved orthogonal test approach assures highest specificity (99.8%); thereby enabling robust serodiagnosis in low-prevalence settings with simple test formats. The inclusion of a calibrator permits accurate quantitative monitoring of antibody concentrations in samples collected at different time points during the acute and convalescent phase of COVID-19 and disclosed antibody level thresholds that correlate well with robust neutralization of authentic SARS-CoV-2 virus., Interpretation: We demonstrate that antigen source and purity strongly impact serotest performance. Comprehensive biotechnology-assisted selection of antigens and in-depth characterisation of the assays allowed us to overcome limitations of simple ELISA-based antibody test formats based on chromometric reporters, to yield comparable assay performance as fully-automated platforms., Funding: WWTF, Project No. COV20-016; BOKU, LBI/LBG., Competing Interests: Declaration of Competing Interest Dr. Klausberger has nothing to disclose. Dr. Duerkop has nothing to disclose. Dr. Haslacher has nothing to disclose. Dr. Wozniak-Knopp has nothing to disclose. Dr. Cserjan-Puschmann has nothing to disclose. Dr. Perkmann has nothing to disclose. Dr. Lingg has nothing to disclose. Dr. Pereira Aguilar has nothing to disclose. Dr. Laurent has nothing to disclose. Dr. De Vos has nothing to disclose. Mag.rer.nat. Hofner has nothing to disclose. Dr. Holzer has nothing to disclose. Mrs. Stadler has nothing to disclose. Dipl.-Ing. Manhart has nothing to disclose. DI Vierlinger has nothing to disclose. Dr. Egger has nothing to disclose. Dipl. Ing. Milchram has nothing to disclose. Dr. Gludovacz has nothing to disclose. Dr. Marx has nothing to disclose. Dipl.-Ing. Köppl has nothing to disclose. Christopher Tauer, BSc has nothing to disclose. Jürgen Beck, MSc reports nothing to disclose. Daniel Maresch has nothing to disclose. Dr. Grünwald-Gruber has nothing to disclose. Mr. Strobl has nothing to disclose. Dr. Satzer has nothing to disclose. Dr. Stadlmayr has nothing to disclose. Ing. Vavra has nothing to disclose. Ms. Huber BSc has nothing to disclose. Dr. Wahrmann has nothing to disclose. Dr. Eskandary has nothing to disclose. Dr. Breyer has nothing to disclose. Dr. Sieghart has nothing to disclose. Dr. Quehenberger reports other from Roche Austria, personal fees from Takeda, outside the submitted work; . Dr. Leitner has nothing to disclose. Dr. Strassl has nothing to disclose. Dr. Egger has nothing to disclose. Dr. IRSARA has nothing to disclose. Dr. Griesmacher has nothing to disclose. Dr. Hoermann has nothing to disclose. Dr. Weiss has nothing to disclose. Dr. Bellmann-Weiler has nothing to disclose. Dr. Löffler-Ragg has nothing to disclose. Dr. Borth has nothing to disclose. Dr. Strasser has nothing to disclose. Dr. Jungbauer has nothing to disclose. Dr. Hahn has nothing to disclose. Dr. Mairhofer reports other from enGenes Biotech GmbH, outside the submitted work; In addition, Dr. Mairhofer has a patent PCT/EP2016/059597-Uncoupling growth and protein production issued. Dr. Hartmann has nothing to disclose. Dr. Binder reports grants from Vienna Business Agency, during the conduct of the study; and Employee of Technoclone Herstellung von Diagnostika und Arzneimitteln GmbH. Dr. Striedner reports other from enGenes GmbH, outside the submitted work; In addition, Dr. Striedner has a patent. US20180282737A1 issued to enGenes GmbH. Dr. Mach has nothing to disclose. Dr. Weinhaeusel has nothing to disclose. Dr. Dieplinger has nothing to disclose. Dr. Grebien has nothing to disclose. Dr. Gerner has nothing to disclose. Dr. Christoph Binder is board member of Technoclone GmbH. Dr. Grabherr has nothing to disclose., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections cause coronavirus disease 2019 (COVID-19) and induce a specific antibody response. Serological assays detecting IgG against the receptor binding domain (RBD) of the spike (S) protein are useful to monitor the immune response after infection or vaccination. The objective of our study was to evaluate the clinical performance of the Siemens SARS-CoV-2 IgG (sCOVG) assay., Methods: Sensitivity and specificity of the Siemens sCOVG test were evaluated on 178 patients with SARS-CoV-2-infection and 160 pre-pandemic samples in comparison with its predecessor test COV2G. Furthermore, correlation with virus neutralization titers was investigated on 134 samples of convalescent COVID-19 patients., Results: Specificity of the sCOVG test was 99.4% and sensitivity was 90.5% (COV2G assay 78.7%; p<0.0001). S1-RBD antibody levels showed a good correlation with virus neutralization titers (r=0.843; p<0.0001) and an overall qualitative agreement of 98.5%. Finally, median S1-RBD IgG levels increase with age and were significantly higher in hospitalized COVID-19 patients (median levels general ward: 25.7 U/mL; intensive care: 59.5 U/mL) than in outpatients (3.8 U/mL; p<0.0001)., Conclusions: Performance characteristics of the sCOVG assay have been improved compared to the predecessor test COV2G. Quantitative SARS-CoV-2 S1-RBD IgG levels could be used as a surrogate for virus neutralization capacity. Further harmonization of antibody quantification might assist to monitor the humoral immune response after COVID-19 disease or vaccination., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Rapid identification of infected subjects is a cornerstone for controlling a pandemic like the current one with the SARS-CoV-2. Easy to handle antigen tests can provide timely results, which is of particular importance in a primary care setting. However, concerns exist regarding their sensitivity, which led us to evaluate four commercially available tests in patients hospitalized for COVID-19., Methods: We analyzed in parallel nasopharyngeal/oropharyngeal swabs from 154 consecutive patients admitted to our department with moderate to severe COVID-19, using quantitative RT-PCR (Cobas, Roche) and up to four antigen tests from different distributors. Antigen test results were linked to Ct (cycle threshold) values as markers for patients' infectivity., Results: We found that two out of four antigen tests correctly identified subjects with high viral loads (Ct≤25), and three out of four tests detected more than 80% of subjects with a Ct≤30, which is considered the threshold for infectivity. However, one test investigated had a poor clinical performance. When investigating subjects with Ct values >30, we found that the antigen test was still positive in up to 45% of those cases., Conclusion: Most antigen tests had a sufficient sensitivity to identify symptomatic subjects infected with SARS-CoV-2 and with transmissible infection. On the other hand, antigen testing may not be suitable to identify loss of infectivity in COVID-19 subjects during follow-up. Newly introduced antigen tests need to be validated in a clinical or primary care setting to define their clinical usefulness., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The diagnosis of COVID-19 relies on the direct detection of SARS-CoV-2 RNA in respiratory specimens by RT-PCR. The pandemic spread of the disease caused an imbalance between demand and supply of materials and reagents needed for diagnostic purposes including swab sets. In a comparative effectiveness study, we conducted serial follow-up swabs in hospitalized laboratory-confirmed COVID-19 patients. We assessed the diagnostic performance of an in-house system developed according to recommendations by the US CDC. In a total of 96 serial swabs, we found significant differences in the accuracy of the different swab systems to generate a positive result in SARS-CoV-2 RT-PCR, ranging from around 50 to 80%. Of note, an in-house swab system was superior to most commercially available sets as reflected by significantly lower Ct values of viral genes. Thus, a simple combination of broadly available materials may enable diagnostic laboratories to bypass global limitations in the supply of swab sets.

Abstract Vaccines against SARS-CoV-2 protect from critical or severe pathogenesis also against new variants of concern (VOCs) such as BA.4 and BA.5, but immediate interventions to avoid viral transmission and subsequent inflammatory reactions are needed. Here we applied the ColdZyme® medical device mouth spray to fully differentiated, polarized human epithelium cultured at an air-liquid interphase (ALI). We found using VOCs BA.1 and BA.4/5 that this device effectively blocked respiratory tissue infection. While infection with these VOCs resulted in intracellular complement activation, thus enhanced inflammation, and drop of transepithelial resistance, these phenomena were prevented by a single administration of this medical device. Thus, ColdZyme® mouth spray significantly shields epithelial integrity, hinders virus infection and blocks in a secondary effect intrinsic complement activation within airway cultures also in terms of the highly contagious VOCs BA.4/5. Crucially, our in vitro data suggest that ColdZyme® mouth spray may have an impact to protect against SARS-CoV-2 transmission, also in case of the Omicron BA.1, BA.4 and BA.5 variants.

Patients with chronic kidney disease (CKD) or immunosuppression are at increased risk of severe SARS-CoV-2 infection. The vaccination of CKD patients has resulted in lower antibody concentrations and possibly reduced protection. However, little information is available on how T-cell-mediated immune response is affected in those patients and how vaccine-induced immune responses can neutralise different SARS-CoV-2 variants. Herein, we studied virus-specific humoral and cellular immune responses after two doses of mRNA-1273 (Moderna) vaccine in 42 patients suffering from CKD, small vessel vasculitis (maintenance phase), or kidney transplant recipients (KT). Serum and PBMCs from baseline and at three months after vaccination were used to determine SARS-CoV-2 S1-specific antibodies, neutralisation titers against SARS-CoV-2 WT, B1.617.2 (delta), and BA.1 (omicron) variants as well as virus-specific T-cells via IFNγ ELISpot assays. We observed a significant increase in quantitative and neutralising antibody titers against SARS-CoV-2 and significantly increased T-cell responses to SARS-CoV-2 S1 antigen after vaccination only in the CKD patients. In patients with vasculitis, neither humoral nor cellular responses were detected. In KT recipients, antibodies and virus neutralisation against WT and delta, but not against omicron BA.1, was assured. Importantly, we found no specific SARS-CoV-2 T-cell response in vasculitis and KT subjects, although unspecific T-cell activation was evident in most patients even before vaccination. While pre-dialysis CKD patients appear to mount an effective immune response for in vitro neutralisation of SARS-CoV-2, KT and vasculitis patients under immunosuppressive therapy were insufficiently protected from SARS-CoV-2 two months after the second dose of an mRNA vaccine. [ABSTRACT FROM AUTHOR]

Immunothrombosis, an excessive inflammatory response with simultaneous overactivation of the coagulation system, is a central pathomechanism in sepsis and COVID-19. It is associated with cellular activation, vascular damage, and microvascular thrombosis, which can lead to multiple organ failure and death. Here, we characterized factors related to immunothrombosis in plasma samples from 78 sepsis patients. In the course of routine clinical testing, SARS-CoV-2 was detected in 14 of these patients. Viral infection was associated with a higher mortality. Both, COVID-19 negative and COVID-19 positive sepsis patients showed increased levels of effectors of immunothrombosis, including platelet factor 4, D-dimer, nucleosomes, citrullinated histone H3, high mobility group box-1 protein, as well as phosphatidylserine-expressing platelet-derived extracellular vesicles, compared to healthy controls (n = 25). Using a 27-plex cytokine bead array, we found that Interleukin (IL)-1ra, IL-6, IL-8, IL-13, tumor necrosis factor (TNF)-α, interferon inducible protein (IP)-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and granulocyte-colony stimulating factor (G-CSF) were elevated in both, COVID-19 negative and COVID-19 positive sepsis patients, as compared to healthy controls. SARS-CoV-2 infection was associated with elevated levels of IP-10, MCP-1, and IL-13, while all other mediators widely overlapped between COVID-19 negative and COVID-19 positive patients. [ABSTRACT FROM AUTHOR]

Reverse transcription polymerase chain reaction (RT-PCR) on respiratory tract swabs has become the gold standard for sensitive and specific detection of influenza virus, respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this retrospective analysis, we report on the successive implementation and routine use of multiplex RT-PCR testing for patients admitted to the Internal Medicine Emergency Department (ED) at a tertiary care center in Western Austria, one of the hotspots in the early coronavirus disease 2019 (COVID-19) pandemic in Europe. Our description focuses on the use of the Cepheid® Xpert® Xpress closed RT-PCR system in point-of-care testing (POCT). Our indications for RT-PCR testing changed during the observation period: From the cold season 2016/2017 until the cold season 2019/2020, we used RT-PCR to diagnose influenza or RSV infection in patients with fever and/or respiratory symptoms. Starting in March 2020, we used the RT-PCR for SARS-CoV-2 and a multiplex version for the combined detection of all these three respiratory viruses to also screen subjects who did not present with symptoms of infection but needed in-hospital medical treatment for other reasons. Expectedly, the switch to a more liberal RT-PCR test strategy resulted in a substantial increase in the number of tests. Nevertheless, we observed an immediate decline in influenza virus and RSV detections in early 2020 that coincided with public SARS-CoV-2 containment measures. In contrast, the extensive use of the combined RT-PCR test enabled us to monitor the re-emergence of influenza and RSV detections, including asymptomatic cases, at the end of 2022 when COVID-19 containment measures were no longer in place. Our analysis of PCR results for respiratory viruses from a real-life setting at an ED provides valuable information on the epidemiology of those infections over several years, their contribution to morbidity and need for hospital admission, the risk for nosocomial introduction of such infection into hospitals from asymptomatic carriers, and guidance as to how general precautions and prophylactic strategies affect the dynamics of those infections. [ABSTRACT FROM AUTHOR]

Introduction: Influenza and the coronavirus disease 2019 (COVID-19) are two potentially severe viral infections causing significant morbidity and mortality. The causative viruses, influenza A/B and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) can cause both pulmonary and extra-pulmonary disease, including cardiovascular involvement. The objective of this study was to determine the levels of cardiac biomarkers in hospitalized patients infected with influenza or COVID-19 and their correlation with secondary outcomes. Methods: We performed a retrospective comparative analysis of cardiac biomarkers in patients hospitalized at our department with influenza or COVID-19 by measuring high-sensitivity troponin-T (hs-TnT) and creatinine kinase (CK) in plasma. Secondary outcomes were intensive care unit (ICU) admission and all-cause in-hospital mortality. Results: We analyzed the data of 250 influenza patients and 366 COVID-19 patients. 58.6% of patients with influenza and 46.2% of patients with COVID-19 presented with increased hs-TnT levels. Patients of both groups with increased hs-TnT levels were significantly more likely to require ICU treatment or to die during their hospital stay. Compared with COVID-19, cardiac biomarkers were significantly higher in patients affected by influenza of all age groups, regardless of pre-existing cardiovascular disease. In patients aged under 65 years, no significant difference in ICU admission and mortality was detected between influenza and COVID-19, whereas significantly more COVID-19 patients 65 years or older died or required intensive care treatment. Conclusions: Our study shows that increased cardiac biomarkers are associated with higher mortality and ICU admission in both, influenza and SARS-CoV-2-infected patients. Cardiac biomarkers are higher in the influenza cohort; however, this does not translate into worse outcomes when compared with the COVID-19 cohort. [ABSTRACT FROM AUTHOR]

Severe coronavirus disease 19 (COVID‐19) manifests with systemic immediate proinflammatory innate immune activation and altered iron turnover. Iron homeostasis, differentiation, and function of myeloid leukocytes are interconnected. Therefore, we characterized the cellularity, surface marker expression, and iron transporter phenotype of neutrophils and monocyte subsets in COVID‐19 patients within 72 h from hospital admission, and analyzed how these parameters relate to infection severity. Between March and November 2020, blood leukocyte samples from hospitalized COVID‐19 patients (n = 48) and healthy individuals (n = 7) were analyzed by flow cytometry enabling comparative analysis of 40 features. Inflammation‐driven neutrophil expansion, depletion of CD16+ nonclassical monocytes, and changes in surface expression of neutrophil and monocyte CD64 and CD86 were associated with COVID‐19 severity. By unsupervised self‐organizing map clustering, four patterns of innate myeloid response were identified and linked to varying levels of systemic inflammation, altered cellular iron trafficking and the severity of disease. These alterations of the myeloid leukocyte compartment during acute COVID‐19 may be hallmarks of inefficient viral control and immune hyperactivation and may help at risk prediction and treatment optimization. [ABSTRACT FROM AUTHOR]

The CovILD study is a prospective, multicenter, observational cohort study to systematically follow up patients after coronavirus disease-2019 (COVID-19). We extensively evaluated 145 COVID-19 patients at 3 follow-up visits scheduled for 60, 100, and 180 days after initial confirmed diagnosis based on typical symptoms and a positive reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We employed comprehensive pulmonary function and laboratory tests, including serum concentrations of IgG against the viral spike (S) glycoprotein, and compared the results to clinical data and chest computed tomography (CT). We found that at the 60 day follow-up, 131 of 145 (90.3%) participants displayed S-specific serum IgG levels above the cut-off threshold. Notably, the highly elevated IgG levels against S glycoprotein positively correlated with biomarkers of immune activation and negatively correlated with pulmonary function and the extent of pulmonary CT abnormalities. Based on the association between serum S glycoprotein-specific IgG and clinical outcome, we generated an S-specific IgG-based recovery score that, when applied in the early convalescent phase, accurately predicted delayed pulmonary recovery after COVID-19. Therefore, we propose that S-specific IgG levels serve as a useful immunological surrogate marker for identifying at-risk individuals with persistent pulmonary injury who may require intensive follow-up care after COVID-19. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic, caused by a novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), emerged at the end of 2019 in China and affected the entire world population, either by infection and its health consequences, or by restrictions in daily life as a consequence of hygiene measures and containment strategies. As of September 2021, more than 231,000.000 infections and 4,740.000 deaths due to COVID-19 have been reported. The infections present with varied clinical symptoms and severity, ranging from asymptomatic course to fatal outcome. Several risk factors for a severe course of the disease have been identified, the most important being age, gender, comorbidities, lifestyle, and genetics. While most patients recover within several weeks, some report persistent symptoms restricting their daily lives and activities, termed as post-COVID. Over the past 18months, we have acquired significant knowledge as reflected by an almost uncountable number of publications on the nature of the underlying virus and its evolution, host responses to infection, modes of transmission, and different clinical presentations of the disease. Along this line, new diagnostic tests and algorithms have been developed paralleled by the search for and clinical evaluation of specific treatments for the different stages of the disease. In addition, preventive non-pharmacological measures have been implemented to control the spread of infection in the community. While an effective antiviral therapy is not yet available, numerous vaccines including novel vaccine technologies have been developed, which show high protection from infection and specifically from a severe course or death from COVID-19. In this review, we tried to provide an up-to-date schematic of COVID-19, including aspects of epidemiology, virology, clinical presentation, diagnostics, therapy, and prevention. [ABSTRACT FROM AUTHOR]

Background and purpose: To assess neurological manifestations and health‐related quality of life (QoL) 3 months after COVID‐19. Methods: In this prospective, multicenter, observational cohort study we systematically evaluated neurological signs and diseases by detailed neurological examination and a predefined test battery assessing smelling disorders (16‐item Sniffin Sticks test), cognitive deficits (Montreal Cognitive Assessment), QoL (36‐item Short Form), and mental health (Hospital Anxiety and Depression Scale, Posttraumatic Stress Disorder Checklist–5) 3 months after disease onset. Results: Of 135 consecutive COVID‐19 patients, 31 (23%) required intensive care unit (ICU) care (severe), 72 (53%) were admitted to the regular ward (moderate), and 32 (24%) underwent outpatient care (mild) during acute disease. At the 3‐month follow‐up, 20 patients (15%) presented with one or more neurological syndromes that were not evident before COVID‐19. These included polyneuro/myopathy (n = 17, 13%) with one patient presenting with Guillain‐Barré syndrome, mild encephalopathy (n = 2, 2%), parkinsonism (n = 1, 1%), orthostatic hypotension (n = 1, 1%), and ischemic stroke (n = 1, 1%). Objective testing revealed hyposmia/anosmia in 57/127 (45%) patients at the 3‐month follow‐up. Self‐reported hyposmia/anosmia was lower (17%) at 3 months, however, improved when compared to the acute disease phase (44%; p < 0.001). At follow‐up, cognitive deficits were apparent in 23%, and QoL was impaired in 31%. Assessment of mental health revealed symptoms of depression, anxiety, and posttraumatic stress disorders in 11%, 25%, and 11%, respectively. Conclusions: Despite recovery from the acute infection, neurological symptoms were prevalent at the 3‐month follow‐up. Above all, smelling disorders were persistent in a large proportion of patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: Since the outbreak of the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) pandemic, several reports indicated neurological involvement in COVID‐19 disease. Muscle involvement has also been reported as evidenced by creatine kinase (CK) elevations and reports of myalgia. Methods: Creatine kinase, markers of inflammation, pre‐existing diseases and statin use were extracted from records of Austrian hospitalised COVID‐19 patients. Disease severity was classified as severe in case of intensive care unit (ICU) admission or mortality. COVID‐19 patients were additionally compared to an historical group of hospitalised influenza patients. Results: Three hundred fifty‐one patients with SARS‐CoV‐2 and 258 with influenza were included in the final analysis. CK was elevated in 27% of COVID‐19 and in 28% of influenza patients. CK was higher in severe COVID‐19 as were markers of inflammation. CK correlated significantly with inflammation markers, which had an independent impact on CK when adjusted for demographic variables and disease severity. Compared to influenza patients, COVID‐19 patients were older, more frequently male, had more comorbidities, and more frequently had a severe disease course. Nevertheless, influenza patients had higher baseline CK than COVID‐19, and 35.7% of intensive care unit (ICU)‐admitted patients had CK levels >1,000 U/L compared to only 4.7% of ICU‐admitted COVID‐19 patients. Conclusions: HyperCKemia occurs in a similar frequency in COVID‐19 and influenza infection. CK levels were lower in COVID‐19 than in influenza in mild and severe disease. CK levels strongly correlate with disease severity and markers of inflammation. To date, it remains unclear whether hyperCKemia is due to a virus‐triggered inflammatory response or direct muscle toxicity. [ABSTRACT FROM AUTHOR]

Background: Male sex is related to increased COVID-19 severity and fatality although confirmed infections are similarly distributed between men and women. The aim of this retrospective analysis was to investigate the impact of sex hormones on disease progression and immune activation in men with COVID-19. Patients and Methods: We studied for effects of sex hormones on disease severity and immune activation in 377 patients (230 men, 147 women) with PCR-confirmed SARS-CoV-2 infections hospitalized at the Innsbruck University Hospital between February and December 2020. Results: Men had more severe COVID-19 with concomitant higher immune system activation upon hospital admission when compared to women. Men with a severe course of infection had lower serum total testosterone (tT) levels whereas luteinizing hormone (LH) and estradiol (E2) levels were within the normal range. tT deficiency was associated with elevated CRP (rs = - 0.567, p < 0.001), IL-6 levels (rs = - 0.563, p < 0.001), lower cholesterol levels (rs = 0.407, p < 0.001) and an increased morbidity and mortality. Men with tT levels < 100 ng/dL had a more than eighteen-fold higher in-hospital mortality risk (OR 18.243 [95%CI 2.301 – 144.639], p = 0.006) compared to men with tT levels > 230 ng/dL. Moreover, while morbidity and mortality showed a positive correlation with E2 levels at admission, we detected a negative correlation with the tT/E2 ratio upon hospital admission. Conclusion: Hospitalized men with COVID-19 present with rather low testosterone levels linked to more advanced immune activation, severe clinical manifestations translating into an increased risk for ICU admission or death. The underlying mechanisms remain elusive but may include infection driven hypogonadism as well as inflammation mediated cholesterol reduction causing gonadotropin suppression and impaired androgen formation. Finally, in elderly late onset hypogonadism might also contribute to lower testosterone levels. [ABSTRACT FROM AUTHOR]

Serological tests detect antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the ongoing coronavirus disease-19 (COVID-19) pandemic. Independent external clinical validation of performance characteristics is of paramount importance. Four fully automated assays, Roche Elecsys Anti-SARS-CoV-2, Abbott SARS-CoV-2 IgG, Siemens SARS-CoV-2 total (COV2T) and SARS-CoV-2 IgG (COV2G) were evaluated using 350 pre-pandemic samples and 700 samples from 245 COVID-19 patients (158 hospitalized, 87 outpatients). All tests showed very high diagnostic specificity. Sensitivities in samples collected at least 14 days after disease onset were slightly lower than manufacturers' claims for Roche (93.0%), Abbott (90.8%), and Siemens COV2T (90.3%), and distinctly lower for Siemens COV2G (78.8%). Concordantly negative results were enriched for immunocompromised patients. ROC curve analyses suggest a lowering of the cut-off index for the Siemens COV2G assay. Finally, the combination of two anti-SARS-CoV-2 antibody assays is feasible when considering borderline reactive results. Thorough on-site evaluation of commercially available serologic tests for detection of antibodies against SARS-CoV-2 remains imperative for laboratories. The potentially impaired sensitivity of the Siemens COV2G necessitates a switch to the company's newly filed SARS-CoV-2 IgG assay for follow-up studies. A combination of tests could be considered in clinical practice. [ABSTRACT FROM AUTHOR]

Background Since the first documented outbreak of a novel severe acute respiratory syndrome inducing Coronavirus in China at the end of 2019 the virus has spread to all continents, leading the WHO to declare a pandemic in March 2020. While this virus primarily targets the alveoli in the lungs, multiple authors have described an increased rate of thrombo-embolic events in affected patients. We present this case of a myocardial infarction with no obstructive coronary atherosclerosis in an otherwise healthy 48-year-old patient. Case summary A 48-year-old female, presenting with chest pain radiating to her left shoulder with no cardiovascular risk factors other than genetic predisposition, was screened for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and tested positive. Although computed tomography angiography excluded obstructive coronary heart disease, cardiac magnetic resonance imaging showed an acute myocardial infarction with no obstructive coronary arteries of the inferior wall. The patient was treated with dual anti-platelet therapy, an angiotensin-converting-enzyme inhibitor and a statin, and assigned to a cardiac rehabilitation program. Conclusion We report a serious thrombo-embolic event during an oligosymptomatic SARS-CoV-2 infection in a healthy, young patient. While these two diseases may have occurred simultaneously, by chance, it is possible that the pro-thrombotic effects of the SARS-CoV-2 infection facilitated the infarction. This case further demonstrates the significant cardiovascular morbidity potentially caused by SARS-CoV-2. [ABSTRACT FROM AUTHOR]

This study evaluates the predictive value of circulating inflammatory markers, especially neopterin, in patients with coronavirus disease 2019 (COVID-19). Within this retrospective analysis of 115 hospitalized COVID-19 patients, elevated neopterin levels upon admission were significantly associated with disease severity, risk for intensive care unit admission, need for mechanical ventilation, and death. Therefore, neopterin is a reliable predictive marker in patients with COVID-19 and may help to improve the clinical management of patients. [ABSTRACT FROM AUTHOR]

Anemia and disturbances of iron metabolism are frequently encountered in patients with COVID-19 and associated with an adverse clinical course. We retrospectively analyzed 645 consecutive COVID-19 patients hospitalized at the Innsbruck University Hospital. Pre-existing anemia was associated with increased risk for in-hospital death. We further found that the decline in hemoglobin levels during hospital stay is more pronounced in patients with signs of hyperinflammation upon admission, the latter being associated with a nearly two-fold higher risk for new onset anemia within one week. Anemia prevalence increased from 44.3% upon admission to 87.8% in patients who were still hospitalized after two weeks. A more distinct decrease in hemoglobin levels was observed in subjects with severe disease, and new-onset anemia was associated with a higher risk for ICU admission. Transferrin levels decreased within the first week of hospitalization in all patients, however, a continuous decline was observed in subjects who died. Hemoglobin, ferritin, and transferrin levels normalized in a median of 122 days after discharge from hospital. This study uncovers pre-existing anemia as well as low transferrin concentrations as risk factors for mortality in hospitalized COVID-19 patients, whereas new-onset anemia during hospitalization is a risk factor for ICU admission. Anemia and iron disturbances are mainly driven by COVID-19 associated inflammation, and cure from infection results in resolution of anemia and normalization of dysregulated iron homeostasis. [ABSTRACT FROM AUTHOR]

The novel Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a global health concern. Vitamin D (VITD) deficiency has been suggested to alter SARS-CoV-2 susceptibility and the course of disease. Thus, we aimed to investigate associations of VITD status to disease presentation within the CovILD registry. This prospective, multicenter, observational study on long-term sequelae includes patients with COVID-19 after hospitalization or outpatients with persistent symptoms. Eight weeks after PCR confirmed diagnosis, a detailed questionnaire, a clinical examination, and laboratory testing, including VITD status, were evaluated. Furthermore, available laboratory specimens close to hospital admission were used to retrospectively analyze 25-hydroxyvitamin D levels at disease onset. A total of 109 patients were included in the analysis (60% males, 40% females), aged 58 ± 14 years. Eight weeks after the onset of COVID-19, a high proportion of patients presented with impaired VITD metabolism and elevated parathyroid hormone (PTH) levels. PTH concentrations were increased in patients who needed intensive care unit (ICU) treatment, while VITD levels were not significantly different between disease severity groups. Low VITD levels at disease onset or at eight-week follow-up were not related to persistent symptom burden, lung function impairment, ongoing inflammation, or more severe CT abnormalities. VITD deficiency is frequent among COVID-19 patients but not associated with disease outcomes. However, individuals with severe disease display a disturbed parathyroid-vitamin-D axis within their recovery phase. The proposed significance of VITD supplementation in the clinical management of COVID-19 remains elusive. [ABSTRACT FROM AUTHOR]

Infections with SARS-CoV-2 can result in severe clinical manifestations. As such patients present with systemic inflammation, we studied the prevalence and predictive value of anemia of inflammation (AI) or functional iron deficiency (FID), originating from immune-mediated alterations of iron homeostasis. Within this retrospective analysis of 259 hospitalized patients with COVID-19, we found that, upon admission, 24.7% were anemic, with the majority suffering from AI (68.8%). Anemia was associated with a significantly higher in-hospital mortality (OR 3.729 (95%CI 1.739–7.995), p = 0.001) but not an increased frequency of intensive care unit (ICU) admission or need for mechanical ventilation. FID was present in 80.0% of patients upon admission, linked to more advanced inflammation and associated with significantly longer hospital stay. Notably, a ferritin/transferrin ratio > 10 predicted a five-fold higher risk of ICU admission and an eight-fold higher risk of the need for mechanical ventilation. Anemia and alterations of iron homeostasis are highly prevalent in hospitalized COVID-19 patients. Iron metabolism biomarkers and hemoglobin can contribute to risk stratification of patients, as initial anemia is associated with increased mortality, whereas alterations of iron homeostasis with a higher ferritin/transferrin ratio reflect more advanced inflammation and predicts subsequent insufficient pulmonary oxygenation with the need for ICU admission and mechanical ventilation. [ABSTRACT FROM AUTHOR]