Special Issue "Viral Markers and the Diagnosis of COVID-19"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "SARS-CoV-2 and COVID-19".

Deadline for manuscript submissions: closed (31 August 2021).

Special Issue Editors

Prof. Dr. Bertram Flehmig
E-Mail Website
Guest Editor
Childrens Hospital, University of Tübingen, Tübingen, Germany
Interests: Hepatitis viruses A, B, C, D, E; Influenza viruses; clinical virology diagnostics and vaccine research; SARS-CoV-2
Prof. Dr. Karin Klingel
E-Mail Website
Guest Editor
Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany
Interests: hepatitis viruses; influenza viruses; human papillomaviruses; COVID-19
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Since the detection of SARS-CoV-2 as the causative agent of COVID-19, enormous scientific activity occurred in the scientific community regarding the development of diagnostic test systems.

Besides the detection of viral RNA by RT-PCR, many of these assay systems have focused on the detection of antibodies in human sera to the SARS-CoV-2 S1 (RBD) protein and the nucleocapsid protein to diagnose this infection. Despite this progress, many open questions have to be answered to define serological markers for the severity of the COVID-19 disease, the long-term follow up of the immune response and the long-term complications of COVID-19.

A new thread for human populations is the newly emerged variants of SARS-CoV-2 having mutations in the Spike S1 protein with the unforeseeable effects of immune escape variants, and variants having the characteristics of higher transmissibility, higher infectivity, higher virulence and pathogenicity, and persistence with longer excretion of the virus.

The measurement of the immune response with various test systems has, to date, mostly been performed semiquantitatively by measuring the S and N proteins. However, in the future, a quantitative determination of the immune response also involving the SARS-CoV-2 M and E proteins and the nonstructural proteins will be desirable, especially in vaccinated persons.

In this Special Issue, manuscripts are welcome that focus on diagnostic test systems, markers for the outcomes of COVID-19, epidemiology, new variants of SARS-CoV-2, transmissibility, and pathogenicity as well as the immune response to the new variants and the immune response after vaccination.

Prof. Dr. Bertram Flehmig
Prof. Dr. Karin Klingel
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • SARS-CoV-2
  • COVID-19
  • diagnostic test systems
  • markers epidemiology
  • new variants
  • transmissibility
  • pathogenicity
  • immune response
  • vaccination

Published Papers (8 papers)

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Research

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Article
Efficacy of Unsupervised Self-Collected Mid-Turbinate FLOQSwabs for the Diagnosis of Coronavirus Disease 2019 (COVID-19)
Viruses 2021, 13(8), 1663; https://doi.org/10.3390/v13081663 - 22 Aug 2021
Viewed by 464
Abstract
Context: The Global Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic has resulted in explosive patterns of transmission in most countries. Nasopharyngeal swabs were the specimen’s collection tools recommended for the diagnosis of SARS-CoV-2 infection, and for monitoring infection outbreaks in communities. Our objective [...] Read more.
Context: The Global Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic has resulted in explosive patterns of transmission in most countries. Nasopharyngeal swabs were the specimen’s collection tools recommended for the diagnosis of SARS-CoV-2 infection, and for monitoring infection outbreaks in communities. Our objective was to report the quality and efficacy of unsupervised self-collected mid turbinate “dry FLOQSwabs” (MT FLOQSwabs) (56380CS01, Copan). There were 111 specimens collected for the study: 36 by health care personnel, from themselves, to verify the quality and efficacy of mid-turbinate swabs; 75 to compare and assess the diagnostic performance, among health care personnel, of nasopharyngeal swabs and self-collected mid-turbinate FLOQSwabs. A collection of 51 specimens was enrolled to define the efficacy of the Testami program (validation). Our analyses demonstrate that self-collected mid-turbinate dry swabs ensure an accuracy of 97.3%, as compared to the standard nasopharyngeal swabs collected by health care workers. Furthermore, the mid-turbinate FLOQSwabs can be stored without medium for six days at room temperature without affecting the molecular diagnosis of the SARS-CoV-2 virus infection. Self-collection of diagnostic specimens at home could offer an avenue to increase testing availability for SARS-CoV-2 infection without asking people to travel to a clinic or a laboratory, thus reducing people’s exposure to infection. Our findings demonstrate that unsupervised self-collection swabs, transported dry, are sensitive, practical and easy-to-use tools and should be considered for diagnosis of SARS-COV-2 and coronavirus disease 2019 (COVID-19) surveillance. Full article
(This article belongs to the Special Issue Viral Markers and the Diagnosis of COVID-19)
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Article
Cell Population Data and Serum Polyclonal Immunoglobulin Free Light Chains in the Assessment of COVID-19 Severity
Viruses 2021, 13(7), 1381; https://doi.org/10.3390/v13071381 - 15 Jul 2021
Viewed by 539
Abstract
Distinguishing between severe and nonsevere COVID-19 to ensure adequate healthcare quality and efficiency is a challenge for the healthcare system. The aim of this study was to assess the usefulness of CBC parameters together with analysis of FLC serum concentration in risk stratification [...] Read more.
Distinguishing between severe and nonsevere COVID-19 to ensure adequate healthcare quality and efficiency is a challenge for the healthcare system. The aim of this study was to assess the usefulness of CBC parameters together with analysis of FLC serum concentration in risk stratification of COVID-19. Materials and methods: CBC was analyzed in 735 COVID ICU, COVID non-ICU, and non-COVID ICU cases. FLC concentration was analyzed in 133 of them. Results: COVID ICU had neutrophils and lymphocytes with the greatest size, granularity, and nucleic acid content. Significant differences in concentrations of κ and λ FLCs were shown between COVID ICU and COVID non-ICU. However, no difference was found in the κ/λ ratio between these groups, and the ratio stayed within the reference value, which indicates the presence of polyclonal FLCs. FLC κ measurement has significant power to distinguish between severe COVID-19 and nonsevere COVID-19 (AUC = 0.7669), with a sensitivity of 86.67% and specificity of 93.33%. The κ coefficients’ odds ratio of 3.0401 was estimated. Conclusion: It can be concluded that the results obtained from the measure of free light immunoglobulin concentration in serum are useful in distinguishing between severe and nonsevere COVID-19. Full article
(This article belongs to the Special Issue Viral Markers and the Diagnosis of COVID-19)
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Article
Long-Term Longitudinal Evaluation of Six Commercial Immunoassays for the Detection of IgM and IgG Antibodies against SARS CoV-2
Viruses 2021, 13(7), 1244; https://doi.org/10.3390/v13071244 - 26 Jun 2021
Viewed by 828
Abstract
The number of serological assays for SARS-CoV-2 has skyrocketed in the past year. Concerns have been raised regarding their performance characteristics, depending on the disease severity and the time of the analysis post-symptom onset (PSO). Thus, independent validations using an unbiased sample selection [...] Read more.
The number of serological assays for SARS-CoV-2 has skyrocketed in the past year. Concerns have been raised regarding their performance characteristics, depending on the disease severity and the time of the analysis post-symptom onset (PSO). Thus, independent validations using an unbiased sample selection are required for meaningful serology data interpretation. We aimed to assess the clinical performance of six commercially available assays, the seroconversion, and the dynamics of the humoral response to SARS-CoV-2 infection. The study included 528 serum samples from 156 patients with follow-up visits up to six months PSO and 161 serum samples from healthy people. The IgG/total antibodies positive percentage increased and remained above 95% after six months when chemiluminescent immunoassay (CLIA) IgG antiS1/S2 and electro-chemiluminescent assay (ECLIA) total antiNP were used. At early time points PSO, chemiluminescent microparticle immunoassay (CMIA) IgM antiS achieved the best sensitivity. IgM and IgG appear simultaneously in most circumstances, and when performed in parallel the sensitivity increases. The severe and the moderate clinical forms were significantly associated with higher seropositivity percentage and antibody levels. High specificity was found in all evaluated assays, but the sensitivity was variable depending on the time PSO, severity of disease, detection method and targeted antigen. Full article
(This article belongs to the Special Issue Viral Markers and the Diagnosis of COVID-19)
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Article
Fast Detection of SARS-CoV-2 RNA Directly from Respiratory Samples Using a Loop-Mediated Isothermal Amplification (LAMP) Test
Viruses 2021, 13(5), 801; https://doi.org/10.3390/v13050801 - 29 Apr 2021
Cited by 2 | Viewed by 828
Abstract
The availability of simple SARS-CoV-2 detection methods is crucial to contain the COVID-19 pandemic. This study examined whether a commercial LAMP assay can reliably detect SARS-CoV-2 genomes directly in respiratory samples without having to extract nucleic acids (NA) beforehand. Nasopharyngeal swabs (NPS, n [...] Read more.
The availability of simple SARS-CoV-2 detection methods is crucial to contain the COVID-19 pandemic. This study examined whether a commercial LAMP assay can reliably detect SARS-CoV-2 genomes directly in respiratory samples without having to extract nucleic acids (NA) beforehand. Nasopharyngeal swabs (NPS, n = 220) were tested by real-time reverse transcription (RT)-PCR and with the LAMP assay. For RT-PCR, NA were investigated. For LAMP, NA from 26 NPS in viral transport medium (VTM) were tested. The other 194 NPS were analyzed directly without prior NA extraction (140 samples in VTM; 54 dry swab samples stirred in phosphate buffered saline). Ten NPS were tested directly by LAMP using a sous-vide cooking unit. The isothermal assay demonstrated excellent specificity (100%) but moderate sensitivity (68.8%), with a positive predictive value of 1 and a negative predictive value of 0.65 for direct testing of NPS in VTM. The use of dry swabs, even without NA extraction, improved the analytical sensitivity; up to 6% of samples showed signs of inhibition. LAMP could be performed successfully with a sous-vide cooking unit. This technique is very fast, requires little laboratory resources, and can replace rapid antigen tests or verify reactive rapid tests on-site. Full article
(This article belongs to the Special Issue Viral Markers and the Diagnosis of COVID-19)
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Article
Development and Clinical Evaluation of an Immunochromatography-Based Rapid Antigen Test (GenBody™ COVAG025) for COVID-19 Diagnosis
Viruses 2021, 13(5), 796; https://doi.org/10.3390/v13050796 - 29 Apr 2021
Cited by 1 | Viewed by 720
Abstract
Antigen tests for SARS-CoV-2 diagnosis are simpler and faster than their molecular counterparts. Clinical validation of such tests is a prerequisite before their field applications. We developed and clinically evaluated an immunochromatographic immunoassay, GenBody™ COVAG025, for the rapid detection of SARS-CoV-2 nucleocapsid (NP) [...] Read more.
Antigen tests for SARS-CoV-2 diagnosis are simpler and faster than their molecular counterparts. Clinical validation of such tests is a prerequisite before their field applications. We developed and clinically evaluated an immunochromatographic immunoassay, GenBody™ COVAG025, for the rapid detection of SARS-CoV-2 nucleocapsid (NP) antigen in two different clinical studies. Retrospectively, 130 residual nasopharyngeal swabs transferred in viral transport medium (VTM), pre-examined for COVID-19 through emergency use authorization (EUA)-approved real-time RT-PCR assay and tested with GenBody™ COVAG025, revealed a sensitivity and specificity of 90.00% (27/30; 95% CI: 73.47% to 97.89%) and 98.00% (98/100; 95% CI: 92.96% to 99.76%), respectively, fulfilling WHO guidelines. Subsequently, the prospective examination of 200 symptomatic and asymptomatic nasopharyngeal swabs, collected on site and tested with GenBody™ COVAG025 and EUA-approved real-time RT-PCR assay simultaneously, revealed a significantly higher sensitivity and specificity of 94.00% (94/100; 95% CI: 87.40% to 97.77%) and 100.00% (100/100; 95% CI: 96.38% to 100.00%), respectively. Clinical sensitivity and specificity were significantly high for samples with Ct values ≤ 30 as well as within 3 days of symptom onset, justifying its dependency on the viral load. Thus, it is assumed this can help with the accurate diagnosis and timely isolation and treatment of patients with COVID-19, contributing to better control of the global pandemic. Full article
(This article belongs to the Special Issue Viral Markers and the Diagnosis of COVID-19)
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Article
Accessible LAMP-Enabled Rapid Test (ALERT) for Detecting SARS-CoV-2
Viruses 2021, 13(5), 742; https://doi.org/10.3390/v13050742 - 23 Apr 2021
Cited by 2 | Viewed by 1348
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has highlighted bottlenecks in large-scale, frequent testing of populations for infections. Polymerase chain reaction (PCR)-based diagnostic tests are expensive, reliant on centralized labs, can take days to deliver results, and are prone to backlogs and supply shortages. [...] Read more.
The coronavirus disease 2019 (COVID-19) pandemic has highlighted bottlenecks in large-scale, frequent testing of populations for infections. Polymerase chain reaction (PCR)-based diagnostic tests are expensive, reliant on centralized labs, can take days to deliver results, and are prone to backlogs and supply shortages. Antigen tests that bind and detect the surface proteins of a virus are rapid and scalable but suffer from high false negative rates. To address this problem, an inexpensive, simple, and robust 60-minute do-it-yourself (DIY) workflow to detect viral RNA from nasal swabs or saliva with high sensitivity (0.1 to 2 viral particles/μL) and specificity (>97% true negative rate) utilizing reverse transcription loop-mediated isothermal amplification (RT-LAMP) was developed. ALERT (Accessible LAMP-Enabled Rapid Test) incorporates the following features: (1) increased shelf-life and ambient temperature storage, compared to liquid reaction mixes, by using wax layers to isolate enzymes from other reagents; (2) improved specificity compared to other LAMP end-point reporting methods, by using sequence-specific QUASR (quenching of unincorporated amplification signal reporters); (3) increased sensitivity, compared to methods without purification through use of a magnetic wand to enable pipette-free concentration of sample RNA and cell debris removal; (4) quality control with a nasopharyngeal-specific mRNA target; and (5) co-detection of other respiratory viruses, such as influenza B, by multiplexing QUASR-modified RT-LAMP primer sets. The flexible nature of the ALERT workflow allows easy, at-home and point-of-care testing for individuals and higher-throughput processing for labs and hospitals. With minimal effort, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific primer sets can be swapped out for other targets to repurpose ALERT to detect other viruses, microorganisms, or nucleic acid-based markers. Full article
(This article belongs to the Special Issue Viral Markers and the Diagnosis of COVID-19)
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Review

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Review
Utility of Routine Laboratory Biomarkers to Detect COVID-19: A Systematic Review and Meta-Analysis
Viruses 2021, 13(5), 803; https://doi.org/10.3390/v13050803 - 30 Apr 2021
Viewed by 777
Abstract
No routine laboratory biomarkers perform well enough in diagnosing COVID-19 in isolation for them to be used as a standalone diagnostic test or to help clinicians prioritize patients for treatment. Instead, other diagnostic tests are needed. The aim of this work was to [...] Read more.
No routine laboratory biomarkers perform well enough in diagnosing COVID-19 in isolation for them to be used as a standalone diagnostic test or to help clinicians prioritize patients for treatment. Instead, other diagnostic tests are needed. The aim of this work was to statistically summarise routine laboratory biomarker measurements in COVID-19-positive and -negative patients to inform future work. A systematic literature review and meta-analysis were performed. The search included names of commonly used, routine laboratory tests in the UK NHS, and focused on research papers reporting laboratory results of patients diagnosed with COVID-19. A random effects meta-analysis of the standardized mean difference between COVID-19-positive and -negative groups was conducted for each biomarker. When comparing reported laboratory biomarker results, we identified decreased white blood cell, neutrophil, lymphocyte, eosinophil, and platelet counts; while lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were elevated in COVID-19-positive compared to COVID-19-negative patients. Differences were identified across a number of routine laboratory biomarkers between COVID-19-positive and -negative patients. Further research is required to identify whether routine laboratory biomarkers can be used in the development of a clinical scoring system to aid with triage of patients. Full article
(This article belongs to the Special Issue Viral Markers and the Diagnosis of COVID-19)
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Other

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Brief Report
Detection of SARS-CoV-2 Derived Small RNAs and Changes in Circulating Small RNAs Associated with COVID-19
Viruses 2021, 13(8), 1593; https://doi.org/10.3390/v13081593 - 11 Aug 2021
Viewed by 610
Abstract
Cleavage of double-stranded RNA is described as an evolutionary conserved host defense mechanism against viral infection. Small RNAs are the product and triggers of post transcriptional gene silencing events. Up until now, the relevance of this mechanism for SARS-CoV-2-directed immune responses remains elusive. [...] Read more.
Cleavage of double-stranded RNA is described as an evolutionary conserved host defense mechanism against viral infection. Small RNAs are the product and triggers of post transcriptional gene silencing events. Up until now, the relevance of this mechanism for SARS-CoV-2-directed immune responses remains elusive. Herein, we used high throughput sequencing to profile the plasma of active and convalescent COVID-19 patients for the presence of small circulating RNAs. The existence of SARS-CoV-2 derived small RNAs in plasma samples of mild and severe COVID-19 cases is described. Clusters of high siRNA abundance were discovered, homologous to the nsp2 3′-end and nsp4 virus sequence. Four virus-derived small RNA sequences have the size of human miRNAs, and a target search revealed candidate genes associated with ageusia and long COVID symptoms. These virus-derived small RNAs were detectable also after recovery from the disease. The additional analysis of circulating human miRNAs revealed differentially abundant miRNAs, discriminating mild from severe cases. A total of 29 miRNAs were reduced or absent in severe cases. Several of these are associated with JAK-STAT response and cytokine storm. Full article
(This article belongs to the Special Issue Viral Markers and the Diagnosis of COVID-19)
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