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2.
PLoS Comput Biol ; 17(2): e1008728, 2021 02.
Article in English | MEDLINE | ID: covidwho-1154072

ABSTRACT

Large-scale serological testing in the population is essential to determine the true extent of the current SARS-CoV-2 pandemic. Serological tests measure antibody responses against pathogens and use predefined cutoff levels that dichotomize the quantitative test measures into sero-positives and negatives and use this as a proxy for past infection. With the imperfect assays that are currently available to test for past SARS-CoV-2 infection, the fraction of seropositive individuals in serosurveys is a biased estimator of the cumulative incidence and is usually corrected to account for the sensitivity and specificity. Here we use an inference method-referred to as mixture-model approach-for the estimation of the cumulative incidence that does not require to define cutoffs by integrating the quantitative test measures directly into the statistical inference procedure. We confirm that the mixture model outperforms the methods based on cutoffs, leading to less bias and error in estimates of the cumulative incidence. We illustrate how the mixture model can be used to optimize the design of serosurveys with imperfect serological tests. We also provide guidance on the number of control and case sera that are required to quantify the test's ambiguity sufficiently to enable the reliable estimation of the cumulative incidence. Lastly, we show how this approach can be used to estimate the cumulative incidence of classes of infections with an unknown distribution of quantitative test measures. This is a very promising application of the mixture-model approach that could identify the elusive fraction of asymptomatic SARS-CoV-2 infections. An R-package implementing the inference methods used in this paper is provided. Our study advocates using serological tests without cutoffs, especially if they are used to determine parameters characterizing populations rather than individuals. This approach circumvents some of the shortcomings of cutoff-based methods at exactly the low cumulative incidence levels and test accuracies that we are currently facing in SARS-CoV-2 serosurveys.


Subject(s)
/methods , /epidemiology , Models, Statistical , Pandemics , Antibodies, Viral/blood , Asymptomatic Infections/epidemiology , /statistics & numerical data , Computational Biology , Computer Simulation , Confidence Intervals , False Negative Reactions , False Positive Reactions , Humans , Incidence , Likelihood Functions , Pandemics/statistics & numerical data , ROC Curve , Reproducibility of Results , Sensitivity and Specificity
3.
J Clin Virol ; 138: 104796, 2021 05.
Article in English | MEDLINE | ID: covidwho-1152481

ABSTRACT

Antigen-detecting rapid diagnostic tests (Ag-RDTs) can complement molecular diagnostics for COVID-19. The recommended temperature for storage of SARS-CoV-2 Ag-RDTs ranges between 2-30 °C. In the global South, mean temperatures can exceed 30 °C. In the global North, Ag-RDTs are often used in external testing facilities at low ambient temperatures. We assessed analytical sensitivity and specificity of eleven commercially-available SARS-CoV-2 Ag-RDTs using different storage and operational temperatures, including short- or long-term storage and operation at recommended temperatures or at either 2-4 °C or at 37 °C. The limits of detection of SARS-CoV-2 Ag-RDTs under recommended conditions ranged from 1.0×106- 5.5×107 genome copies/mL of infectious SARS-CoV-2 cell culture supernatant. Despite long-term storage at recommended conditions, 10 min pre-incubation of Ag-RDTs and testing at 37 °C resulted in about ten-fold reduced sensitivity for five out of 11 SARS-CoV-2 Ag-RDTs, including both Ag-RDTs currently listed for emergency use by the World Health Organization. After 3 weeks of storage at 37 °C, eight of the 11 SARS-CoV-2 Ag-RDTs exhibited about ten-fold reduced sensitivity. Specificity of SARS-CoV-2 Ag-RDTs using cell culture supernatant from common respiratory viruses was not affected by storage and testing at 37 °C, whereas false-positive results occurred at outside temperatures of 2-4 °C for two out of six tested Ag-RDTs, again including an Ag-RDT recommended by the WHO. In summary, elevated temperatures impair sensitivity, whereas low temperatures impair specificity of SARS-CoV-2 Ag-RDTs. Consequences may include false-negative test results at clinically relevant virus concentrations compatible with transmission and false-positive results entailing unwarranted quarantine assignments. Storage and operation of SARS-CoV-2 Ag-RDTs at recommended conditions is essential for successful usage during the pandemic.


Subject(s)
/diagnosis , Diagnostic Tests, Routine , Reagent Kits, Diagnostic , Cold Temperature/adverse effects , False Negative Reactions , False Positive Reactions , Hot Temperature/adverse effects , Humans , Sensitivity and Specificity
4.
Health Technol Assess ; 25(21): 1-68, 2021 03.
Article in English | MEDLINE | ID: covidwho-1150683

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019. At the time of writing (October 2020), the number of cases of COVID-19 had been approaching 38 million and more than 1 million deaths were attributable to it. SARS-CoV-2 appears to be highly transmissible and could rapidly spread in hospital wards. OBJECTIVE: The work undertaken aimed to estimate the clinical effectiveness and cost-effectiveness of viral detection point-of-care tests for detecting SARS-CoV-2 compared with laboratory-based tests. A further objective was to assess occupancy levels in hospital areas, such as waiting bays, before allocation to an appropriate bay. PERSPECTIVE/SETTING: The perspective was that of the UK NHS in 2020. The setting was a hypothetical hospital with an accident and emergency department. METHODS: An individual patient model was constructed that simulated the spread of disease and mortality within the hospital and recorded occupancy levels. Thirty-two strategies involving different hypothetical SARS-CoV-2 tests were modelled. Recently published desirable and acceptable target product profiles for SARS-CoV-2 point-of-care tests were modelled. Incremental analyses were undertaken using both incremental cost-effectiveness ratios and net monetary benefits, and key patient outcomes, such as death and intensive care unit care, caused directly by COVID-19 were recorded. RESULTS: A SARS-CoV-2 point-of-care test with a desirable target product profile appears to have a relatively small number of infections, a low occupancy level within the waiting bays, and a high net monetary benefit. However, if hospital laboratory testing can produce results in 6 hours, then the benefits of point-of-care tests may be reduced. The acceptable target product profiles performed less well and had lower net monetary benefits than both a laboratory-based test with a 24-hour turnaround time and strategies using data from currently available SARS-CoV-2 point-of-care tests. The desirable and acceptable point-of-care test target product profiles had lower requirement for patients to be in waiting bays before being allocated to an appropriate bay than laboratory-based tests, which may be of high importance in some hospitals. Tests that appeared more cost-effective also had better patient outcomes. LIMITATIONS: There is considerable uncertainty in the values for key parameters within the model, although calibration was undertaken in an attempt to mitigate this. The example hospital simulated will also not match those of decision-makers deciding on the clinical effectiveness and cost-effectiveness of introducing SARS-CoV-2 point-of-care tests. Given these limitations, the results should be taken as indicative rather than definitive, particularly cost-effectiveness results when the relative cost per SARS-CoV-2 point-of-care test is uncertain. CONCLUSIONS: Should a SARS-CoV-2 point-of-care test with a desirable target product profile become available, this appears promising, particularly when the reduction on the requirements for waiting bays before allocation to a SARS-CoV-2-infected bay, or a non-SARS-CoV-2-infected bay, is considered. The results produced should be informative to decision-makers who can identify the results most pertinent to their specific circumstances. FUTURE WORK: More accurate results could be obtained when there is more certainty on the diagnostic accuracy of, and the reduction in time to test result associated with, SARS-CoV-2 point-of-care tests, and on the impact of these tests on occupancy of waiting bays and isolation bays. These parameters are currently uncertain. FUNDING: This report was commissioned by the National Institute for Health Research (NIHR) Evidence Synthesis programme as project number 132154. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 21. See the NIHR Journals Library website for further project information.


Subject(s)
/diagnosis , Emergency Service, Hospital/organization & administration , Patient Admission , Point-of-Care Testing/economics , Point-of-Care Testing/standards , /epidemiology , Cost-Benefit Analysis , Emergency Service, Hospital/economics , Emergency Service, Hospital/standards , False Negative Reactions , False Positive Reactions , Humans , State Medicine , United Kingdom
5.
PLoS One ; 16(3): e0248920, 2021.
Article in English | MEDLINE | ID: covidwho-1150550

ABSTRACT

BACKGROUND: Tests are scarce resources, especially in low and middle-income countries, and the optimization of testing programs during a pandemic is critical for the effectiveness of the disease control. Hence, we aim to use the combination of symptoms to build a predictive model as a screening tool to identify people and areas with a higher risk of SARS-CoV-2 infection to be prioritized for testing. MATERIALS AND METHODS: We performed a retrospective analysis of individuals registered in "Dados do Bem," a Brazilian app-based symptom tracker. We applied machine learning techniques and provided a SARS-CoV-2 infection risk map of Rio de Janeiro city. RESULTS: From April 28 to July 16, 2020, 337,435 individuals registered their symptoms through the app. Of these, 49,721 participants were tested for SARS-CoV-2 infection, being 5,888 (11.8%) positive. Among self-reported symptoms, loss of smell (OR[95%CI]: 4.6 [4.4-4.9]), fever (2.6 [2.5-2.8]), and shortness of breath (2.1 [1.6-2.7]) were independently associated with SARS-CoV-2 infection. Our final model obtained a competitive performance, with only 7% of false-negative users predicted as negatives (NPV = 0.93). The model was incorporated by the "Dados do Bem" app aiming to prioritize users for testing. We developed an external validation in the city of Rio de Janeiro. We found that the proportion of positive results increased significantly from 14.9% (before using our model) to 18.1% (after the model). CONCLUSIONS: Our results showed that the combination of symptoms might predict SARS-Cov-2 infection and, therefore, can be used as a tool by decision-makers to refine testing and disease control strategies.


Subject(s)
/diagnosis , Machine Learning , Adult , Brazil , /virology , Dyspnea/etiology , False Negative Reactions , False Positive Reactions , Female , Fever/etiology , Humans , Male , Middle Aged , Mobile Applications , Registries , Retrospective Studies , Risk , Self Report
6.
Cochrane Database Syst Rev ; 3: CD013705, 2021 03 24.
Article in English | MEDLINE | ID: covidwho-1147548

ABSTRACT

BACKGROUND: Accurate rapid diagnostic tests for SARS-CoV-2 infection could contribute to clinical and public health strategies to manage the COVID-19 pandemic. Point-of-care antigen and molecular tests to detect current infection could increase access to testing and early confirmation of cases, and expediate clinical and public health management decisions that may reduce transmission. OBJECTIVES: To assess the diagnostic accuracy of point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups. SEARCH METHODS: Electronic searches of the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) were undertaken on 30 Sept 2020. We checked repositories of COVID-19 publications and included independent evaluations from national reference laboratories, the Foundation for Innovative New Diagnostics and the Diagnostics Global Health website to 16 Nov 2020. We did not apply language restrictions. SELECTION CRITERIA: We included studies of people with either suspected SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen or molecular tests suitable for a point-of-care setting (minimal equipment, sample preparation, and biosafety requirements, with results within two hours of sample collection). We included all reference standards that define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction (RT-PCR) tests and established diagnostic criteria). DATA COLLECTION AND ANALYSIS: Studies were screened independently in duplicate with disagreements resolved by discussion with a third author. Study characteristics were extracted by one author and checked by a second; extraction of study results and assessments of risk of bias and applicability (made using the QUADAS-2 tool) were undertaken independently in duplicate. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and pooled data using the bivariate model separately for antigen and molecular-based tests. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status. MAIN RESULTS: Seventy-eight study cohorts were included (described in 64 study reports, including 20 pre-prints), reporting results for 24,087 samples (7,415 with confirmed SARS-CoV-2). Studies were mainly from Europe (n = 39) or North America (n = 20), and evaluated 16 antigen and five molecular assays. We considered risk of bias to be high in 29 (50%) studies because of participant selection; in 66 (85%) because of weaknesses in the reference standard for absence of infection; and in 29 (45%) for participant flow and timing. Studies of antigen tests were of a higher methodological quality compared to studies of molecular tests, particularly regarding the risk of bias for participant selection and the index test. Characteristics of participants in 35 (45%) studies differed from those in whom the test was intended to be used and the delivery of the index test in 39 (50%) studies differed from the way in which the test was intended to be used. Nearly all studies (97%) defined the presence or absence of SARS-CoV-2 based on a single RT-PCR result, and none included participants meeting case definitions for probable COVID-19. Antigen tests Forty-eight studies reported 58 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies. There were differences between symptomatic (72.0%, 95% CI 63.7% to 79.0%; 37 evaluations; 15530 samples, 4410 cases) and asymptomatic participants (58.1%, 95% CI 40.2% to 74.1%; 12 evaluations; 1581 samples, 295 cases). Average sensitivity was higher in the first week after symptom onset (78.3%, 95% CI 71.1% to 84.1%; 26 evaluations; 5769 samples, 2320 cases) than in the second week of symptoms (51.0%, 95% CI 40.8% to 61.0%; 22 evaluations; 935 samples, 692 cases). Sensitivity was high in those with cycle threshold (Ct) values on PCR ≤25 (94.5%, 95% CI 91.0% to 96.7%; 36 evaluations; 2613 cases) compared to those with Ct values >25 (40.7%, 95% CI 31.8% to 50.3%; 36 evaluations; 2632 cases). Sensitivity varied between brands. Using data from instructions for use (IFU) compliant evaluations in symptomatic participants, summary sensitivities ranged from 34.1% (95% CI 29.7% to 38.8%; Coris Bioconcept) to 88.1% (95% CI 84.2% to 91.1%; SD Biosensor STANDARD Q). Average specificities were high in symptomatic and asymptomatic participants, and for most brands (overall summary specificity 99.6%, 95% CI 99.0% to 99.8%). At 5% prevalence using data for the most sensitive assays in symptomatic people (SD Biosensor STANDARD Q and Abbott Panbio), positive predictive values (PPVs) of 84% to 90% mean that between 1 in 10 and 1 in 6 positive results will be a false positive, and between 1 in 4 and 1 in 8 cases will be missed. At 0.5% prevalence applying the same tests in asymptomatic people would result in PPVs of 11% to 28% meaning that between 7 in 10 and 9 in 10 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed. No studies assessed the accuracy of repeated lateral flow testing or self-testing. Rapid molecular assays Thirty studies reported 33 evaluations of five different rapid molecular tests. Sensitivities varied according to test brand. Most of the data relate to the ID NOW and Xpert Xpress assays. Using data from evaluations following the manufacturer's instructions for use, the average sensitivity of ID NOW was 73.0% (95% CI 66.8% to 78.4%) and average specificity 99.7% (95% CI 98.7% to 99.9%; 4 evaluations; 812 samples, 222 cases). For Xpert Xpress, the average sensitivity was 100% (95% CI 88.1% to 100%) and average specificity 97.2% (95% CI 89.4% to 99.3%; 2 evaluations; 100 samples, 29 cases). Insufficient data were available to investigate the effect of symptom status or time after symptom onset. AUTHORS' CONCLUSIONS: Antigen tests vary in sensitivity. In people with signs and symptoms of COVID-19, sensitivities are highest in the first week of illness when viral loads are higher. The assays shown to meet appropriate criteria, such as WHO's priority target product profiles for COVID-19 diagnostics ('acceptable' sensitivity ≥ 80% and specificity ≥ 97%), can be considered as a replacement for laboratory-based RT-PCR when immediate decisions about patient care must be made, or where RT-PCR cannot be delivered in a timely manner. Positive predictive values suggest that confirmatory testing of those with positive results may be considered in low prevalence settings. Due to the variable sensitivity of antigen tests, people who test negative may still be infected. Evidence for testing in asymptomatic cohorts was limited. Test accuracy studies cannot adequately assess the ability of antigen tests to differentiate those who are infectious and require isolation from those who pose no risk, as there is no reference standard for infectiousness. A small number of molecular tests showed high accuracy and may be suitable alternatives to RT-PCR. However, further evaluations of the tests in settings as they are intended to be used are required to fully establish performance in practice. Several important studies in asymptomatic individuals have been reported since the close of our search and will be incorporated at the next update of this review. Comparative studies of antigen tests in their intended use settings and according to test operator (including self-testing) are required.


Subject(s)
Antigens, Viral/analysis , /diagnosis , Molecular Diagnostic Techniques/methods , Point-of-Care Systems , /immunology , Adult , Asymptomatic Infections , Bias , Child , Cohort Studies , False Negative Reactions , False Positive Reactions , Humans , Molecular Diagnostic Techniques/standards , Predictive Value of Tests , Reference Standards , Sensitivity and Specificity
7.
Virus Res ; 297: 198398, 2021 05.
Article in English | MEDLINE | ID: covidwho-1142296

ABSTRACT

Commercially available reverse transcription-polymerase chain reaction (RT-PCR) kits are being used as an important tool to diagnose SARS-CoV-2 infection in clinical laboratories worldwide. However, some kits lack sufficient clinical evaluation due to the need for emergency use caused by the current COVID-19 pandemic. Here we found that a novel insertion/deletion mutation in the nucleocapsid (N) gene of SARS-CoV-2 samples is a cause of negative results for the N gene in a widely used assay that received emergency use authorization (EUA) from US FDA and Conformite Europeenne-in vitro diagnostics (CE-IVD) from EU. Although SARS-CoV-2 is diagnosed positive by other target probes in the assay, our findings provide an evidence of the genetic variability and rapid evolution of SARS-CoV-2 as well as a reference in designing commercial RT-PCR assays.


Subject(s)
/virology , INDEL Mutation , /genetics , /diagnosis , False Negative Reactions , Genes, Viral , Humans , Mass Screening , Pandemics , RNA, Viral/analysis , Reverse Transcriptase Polymerase Chain Reaction , /isolation & purification
8.
Medicina (Kaunas) ; 57(3)2021 Mar 20.
Article in English | MEDLINE | ID: covidwho-1143533

ABSTRACT

Reverse transcriptase polymerase chain reaction (RT-PCR) negative results in the upper respiratory tract represent a major concern for the clinical management of coronavirus disease 2019 (COVID-19) patients. Herein, we report the case of a 43-years-old man with a strong clinical suspicion of COVID-19, who resulted in being negative to multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR tests performed on different oropharyngeal and nasopharyngeal swabs, despite serology having confirmed the presence of SARS-CoV-2 IgM. The patient underwent a chest computed tomography (CT) that showed typical imaging findings of COVID-19 pneumonia. The presence of viral SARS-CoV-2 was confirmed only by performing a SARS-CoV-2 RT-PCR test on stool. Performing of SARS-CoV-2 RT-PCR test on fecal samples can be a rapid and useful approach to confirm COVID-19 diagnosis in cases where there is an apparent discrepancy between COVID-19 clinical symptoms coupled with chest CT and SARS-CoV-2 RT-PCR tests' results on samples from the upper respiratory tract.


Subject(s)
/diagnosis , Feces/chemistry , Lung/diagnostic imaging , Nasopharynx/chemistry , Oropharynx/chemistry , RNA, Viral/isolation & purification , Adult , Antibodies, Viral/immunology , False Negative Reactions , Feces/virology , Humans , Immunoglobulin M/immunology , Male , Nasopharynx/virology , Oropharynx/virology , Specimen Handling , Tomography, X-Ray Computed
9.
Clin Rev Allergy Immunol ; 59(1): 89-100, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-1139384

ABSTRACT

The COVID-19 pandemic is a significant global event in the history of infectious diseases. The SARS-CoV-2 appears to have originated from bats but is now easily transmissible among humans, primarily through droplet or direct contact. Clinical features of COVID-19 include high fever, cough, and fatigue which may progress to ARDS. Respiratory failure can occur rapidly after this. The primary laboratory findings include lymphopenia and eosinopenia. Elevated D-dimer, procalcitonin, and CRP levels may correlate with disease severity. Imaging findings include ground-glass opacities and patchy consolidation on CT scan. Mortality is higher in patients with hypertension, cardiac disease, diabetes mellitus, cancer, and COPD. Elderly patients are more susceptible to severe disease and death, while children seem to have lower rates of infection and lower mortality. Diagnostic criteria and the identification of persons under investigation have evolved as more data has emerged. However, the approach to diagnosis is still very variable from region to region, country to country, and even among different hospitals in the same city. The importance of a clinical pathway to implement the most effective and relevant diagnostic strategy is of critical importance to establish the control of this virus that is responsible for more and more deaths each day.


Subject(s)
Antibodies, Viral/immunology , Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Lung/diagnostic imaging , Pneumonia, Viral/diagnosis , RNA, Viral/analysis , Algorithms , Betacoronavirus/immunology , Critical Pathways , Early Diagnosis , Evidence-Based Practice , False Negative Reactions , Humans , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Medical History Taking , Pandemics , Patient Isolation , Quarantine , Real-Time Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/methods , Serologic Tests/methods , Severity of Illness Index , Tomography, X-Ray Computed
10.
J Clin Virol ; 137: 104789, 2021 04.
Article in English | MEDLINE | ID: covidwho-1126918

ABSTRACT

BACKGROUND: Rapid antigen tests (RATs) may be included in national strategies for handling the SARS-CoV-2 pandemic, as they provide test results rapidly, are easily performed outside laboratories, and enable immediate contract tracing. However, before implementation further clinical evaluation of test sensitivity is warranted. OBJECTIVES: To examine the performance of Abbott's Panbio™ COVID-19 Ag Rapid Test Device for SARS-CoV-2 testing in a low to medium prevalence setting in Norway. STUDY DESIGN: A prospective study comparing the results of the Panbio RAT with PCR in 4857 parallel samples collected at a SARS-CoV-2 test station in Oslo, and from COVID-19 outbreaks in six Norwegian municipalities. RESULTS: A total of 4857 cases were included in the study; 3991 and 866 cases from the test station and the outbreak municipalities, respectively. The prevalence at the test station in Oslo was 6.3 %, and the overall sensitivity of the RAT was 74 %. Increased sensitivity was observed in patients who experienced symptoms (79 %) and when considering samples with viral loads above estimated level of infectivity (84 %), while it was lower in asymptomatic persons (55 %). In the outbreak municipalities, the overall prevalence was 6.9 %, and the total sensitivity of the RAT was 70 %. CONCLUSIONS: Our results indicate that the test correctly identified most infectious individuals. Nevertheless, the sensitivity is considerably lower than for PCR, and it is important that the limitations of the test are kept in mind in the follow-up of tested individuals.


Subject(s)
Antigens, Viral/analysis , /diagnosis , /isolation & purification , /epidemiology , /methods , False Negative Reactions , False Positive Reactions , Humans , Norway/epidemiology , Prospective Studies , Sensitivity and Specificity , Viral Load
11.
Clin Radiol ; 76(5): 384-390, 2021 05.
Article in English | MEDLINE | ID: covidwho-1126789

ABSTRACT

AIM: To report an audit of the evaluation of suspected, unconfirmed cases of COVID-19 including chest computed tomography (CT), as compared to World Health Organization recommendations. METHODS: A clinical audit was undertaken examining the evaluation of patients with suspected COVID-19 with negative SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) results, with comparison to WHO recommendations. A retrospective chart review was undertaken for 90 patients examining investigations, in particular CT, used to clarify the diagnosis. RESULTS: Ninety patients underwent additional investigation. Seventy-five per cent adherence to WHO recommendations was observed. Fifty-two men (57.78%) and 38 (42.22%) women were investigated, with a median age of 69 years (range 20-96 years). Seventy-nine chest CT examinations demonstrated positive, indeterminate, and negative rates for COVID-19 of 3.79%, 24.1%, and 72.15% respectively. Three patients had discordant swab results with initially negative and subsequently positive results for SARS-CoV-2, resulting in false-negative rates of 5.1% for those retested. Combining discordant RT-PCR swab results, positive radiology, and patients treated as COVID-19-positive due to indeterminate radiology and highly consistent symptoms, resulted in a false-negative rate for initial SARS-CoV-2 RT-PCR swabs of 16.67%. CONCLUSION: Seventy-five per cent compliance with relevant WHO guidance and a false-negative rate for initial swabs of 16.67% was demonstrated. Further evidence is needed to fully determine the utility of chest CT in the diagnosis of COVID-19 in the context of initial false-negative RT-PCR results.


Subject(s)
/diagnostic imaging , Critical Pathways , Guideline Adherence , Lung/diagnostic imaging , Practice Guidelines as Topic , Tomography, X-Ray Computed , Adult , Aged , Aged, 80 and over , False Negative Reactions , Female , Humans , Male , Medical Audit , Middle Aged , Patient Care Team , Retrospective Studies , World Health Organization , Young Adult
12.
PLoS Comput Biol ; 17(3): e1008688, 2021 03.
Article in English | MEDLINE | ID: covidwho-1125385

ABSTRACT

Outbreaks of SARS-CoV-2 are threatening the health care systems of several countries around the world. The initial control of SARS-CoV-2 epidemics relied on non-pharmaceutical interventions, such as social distancing, teleworking, mouth masks and contact tracing. However, as pre-symptomatic transmission remains an important driver of the epidemic, contact tracing efforts struggle to fully control SARS-CoV-2 epidemics. Therefore, in this work, we investigate to what extent the use of universal testing, i.e., an approach in which we screen the entire population, can be utilized to mitigate this epidemic. To this end, we rely on PCR test pooling of individuals that belong to the same households, to allow for a universal testing procedure that is feasible with the limited testing capacity. We evaluate two isolation strategies: on the one hand pool isolation, where we isolate all individuals that belong to a positive PCR test pool, and on the other hand individual isolation, where we determine which of the individuals that belong to the positive PCR pool are positive, through an additional testing step. We evaluate this universal testing approach in the STRIDE individual-based epidemiological model in the context of the Belgian COVID-19 epidemic. As the organisation of universal testing will be challenging, we discuss the different aspects related to sample extraction and PCR testing, to demonstrate the feasibility of universal testing when a decentralized testing approach is used. We show through simulation, that weekly universal testing is able to control the epidemic, even when many of the contact reductions are relieved. Finally, our model shows that the use of universal testing in combination with stringent contact reductions could be considered as a strategy to eradicate the virus.


Subject(s)
/methods , /prevention & control , Epidemics/prevention & control , Belgium/epidemiology , /statistics & numerical data , Computational Biology , Computer Simulation , Contact Tracing/methods , Contact Tracing/statistics & numerical data , Contact Tracing/trends , False Negative Reactions , Family Characteristics , Feasibility Studies , Humans , Mass Screening/methods , Mass Screening/statistics & numerical data , Mass Screening/trends , Models, Statistical , Quarantine/methods , Quarantine/statistics & numerical data , Quarantine/trends , Travel
13.
Viruses ; 13(3)2021 03 11.
Article in English | MEDLINE | ID: covidwho-1124954

ABSTRACT

Control strategies that employ real time polymerase chain reaction (RT-PCR) tests for the diagnosis and surveillance of COVID-19 epidemic are inefficient in fighting the epidemic due to high cost, delays in obtaining results, and the need of specialized personnel and equipment for laboratory processing. Cheaper and faster alternatives, such as antigen and paper-strip tests, have been proposed. They return results rapidly, but have lower sensitivity thresholds for detecting virus. To quantify the effects of the tradeoffs between sensitivity, cost, testing frequency, and delay in test return on the overall course of an outbreak, we built a multi-scale immuno-epidemiological model that connects the virus profile of infected individuals with transmission and testing at the population level. We investigated various randomized testing strategies and found that, for fixed testing capacity, lower sensitivity tests with shorter return delays slightly flatten the daily incidence curve and delay the time to the peak daily incidence. However, compared with RT-PCR testing, they do not always reduce the cumulative case count at half a year into the outbreak. When testing frequency is increased to account for the lower cost of less sensitive tests, we observe a large reduction in cumulative case counts, from 55.4% to as low as 1.22% half a year into the outbreak. The improvement is preserved even when the testing budget is reduced by one half or one third. Our results predict that surveillance testing that employs low-sensitivity tests at high frequency is an effective tool for epidemic control.


Subject(s)
/statistics & numerical data , /genetics , /epidemiology , /economics , Epidemics , False Negative Reactions , Humans , Models, Theoretical , Polymerase Chain Reaction/economics , Polymerase Chain Reaction/methods , Polymerase Chain Reaction/standards , Polymerase Chain Reaction/statistics & numerical data , /physiology , Sensitivity and Specificity
14.
J Appl Lab Med ; 6(2): 421-428, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1120035

ABSTRACT

BACKGROUND: Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcription PCR is the primary method to diagnose coronavirus disease 2019 (COVID-19). However, the analytic sensitivity required is not well defined and it is unclear how available assays compare. METHODS: For the Abbott RealTime SARS-CoV-2 assay (m2000; Abbott Molecular), we determined that it could detect viral concentrations as low as 26 copies/mL, we defined the relationship between cycle number and viral concentrations, and we tested naso- and oropharyngeal swab specimens from 8538 consecutive individuals. Using the m2000 as a reference assay method, we described the distribution of viral concentrations in these patients. We then used selected clinical specimens to determine the positive percent agreement of 2 other assays with more rapid turnaround times [Cepheid Xpert Xpress (GeneXpert; Cepheid); n = 27] and a laboratory developed test on the Luminex ARIES system [ARIES LDT (Luminex); n = 50] as a function of virus concentrations, from which we projected their false-negative rates in our patient population. RESULTS: SARS-CoV-2 was detected in 27% (95% CI: 26%-28%) of all specimens. Estimated viral concentrations were widely distributed, and 17% (95% CI: 16%-19%) of positive individuals had viral concentrations <845 copies/mL. Positive percent agreement was strongly related to viral concentration, and reliable detection (i.e., ≥95%) was observed at concentrations >100 copies/mL for the GeneXpert but not the ARIES LDT, corresponding to projected false-negative rates of 4% (95% CI: 0%-21%) and 27% (95% CI: 11%-46%), respectively. CONCLUSIONS: Substantial proportions of clinical specimens have low to moderate viral concentrations and may be missed by methods with less analytic sensitivity.


Subject(s)
/instrumentation , Reagent Kits, Diagnostic , Real-Time Polymerase Chain Reaction/instrumentation , /isolation & purification , Adult , Aged , Aged, 80 and over , False Negative Reactions , Female , Humans , Limit of Detection , Male , Middle Aged , RNA, Viral/isolation & purification , Reproducibility of Results , Retrospective Studies , /genetics
15.
JAMA Otolaryngol Head Neck Surg ; 147(4): 404-405, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1118073
16.
Korean J Radiol ; 21(4): 505-508, 2020 04.
Article in English | MEDLINE | ID: covidwho-1110277

ABSTRACT

The epidemic of 2019 novel coronavirus, later named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still gradually spreading worldwide. The nucleic acid test or genetic sequencing serves as the gold standard method for confirmation of infection, yet several recent studies have reported false-negative results of real-time reverse-transcriptase polymerase chain reaction (rRT-PCR). Here, we report two representative false-negative cases and discuss the supplementary role of clinical data with rRT-PCR, including laboratory examination results and computed tomography features. Coinfection with SARS-COV-2 and other viruses has been discussed as well.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/virology , Pneumonia, Viral/virology , Reverse Transcriptase Polymerase Chain Reaction , Adult , Betacoronavirus/isolation & purification , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/diagnostic imaging , Deep Learning , False Negative Reactions , Humans , Infant , Male , Pneumonia, Viral/diagnostic imaging , Tomography, X-Ray Computed
17.
JAMA Otolaryngol Head Neck Surg ; 147(4): 403, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1107451
18.
Sci Rep ; 11(1): 4310, 2021 02 22.
Article in English | MEDLINE | ID: covidwho-1096332

ABSTRACT

Patients requiring diagnostic testing for coronavirus disease 2019 (COVID-19) are routinely assessed by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) amplification of Sars-CoV-2 virus RNA extracted from oro/nasopharyngeal swabs. Despite the good specificity of the assays certified for SARS-CoV-2 molecular detection, and a theoretical sensitivity of few viral gene copies per reaction, a relatively high rate of false negatives continues to be reported. This is an important challenge in the management of patients on hospital admission and for correct monitoring of the infectivity after the acute phase. In the present report, we show that the use of digital PCR, a high sensitivity method to detect low amplicon numbers, allowed us to correctly detecting infection in swab material in a significant number of false negatives. We show that the implementation of digital PCR methods in the diagnostic assessment of COVID-19 could resolve, at least in part, this timely issue.


Subject(s)
/diagnosis , False Negative Reactions , Real-Time Polymerase Chain Reaction/methods , /pathogenicity , Adult , Aged , /genetics , Diagnostic Tests, Routine/methods , Female , Humans , Male , Middle Aged , Sensitivity and Specificity , Tomography, X-Ray Computed
19.
J Clin Virol ; 136: 104762, 2021 03.
Article in English | MEDLINE | ID: covidwho-1091784

ABSTRACT

BACKGROUND: Confirmatory testing of SARS-CoV-2 results is essential to reduce false positives, but comes at a cost of significant extra workload for laboratories and increased turnaround time. A balance must be sought. We analysed our confirmatory testing pathway to produce a more refined approach in preparation for rising case numbers. METHODS: Over a 10-week low prevalence period we performed confirmatory testing on all newly positive results. Turnaround time was measured and results were analysed to identify a threshold that could be applied as a cut-off for future confirmatory testing and reduce overall workload for the laboratory. RESULTS: Between 22/06/20 and 31/08/20 confirmatory testing was performed on 108 newly positive samples, identifying 32 false positive results (30 %). Turnaround time doubled, increasing by an extra 17 h. There was a highly statistically significant difference between initial Relative Light Unit (RLU) of results that confirmed compared to those that did not, 1176 vs 721 (P < 0.00001). RLU = 1000 was identified as a suitable threshold for confirmatory testing in our laboratory: with RLU ≥ 1000, 55/56 (98 %) confirmed as positive, whereas with RLU < 1000 only 12/38 (32 %) confirmed. CONCLUSIONS: False positive SARS-CoV-2 tests can be identified by confirmatory testing, yet this may significantly delay results. Establishing a threshold for confirmatory testing streamlines this process to focus only on samples where it is most required. We advise all laboratories to follow a similar process to identify thresholds that trigger confirmatory testing for their own assays, increasing accuracy while maintaining efficiency for when case numbers are high.


Subject(s)
/methods , /isolation & purification , False Negative Reactions , False Positive Reactions , Humans , Real-Time Polymerase Chain Reaction/methods , Sensitivity and Specificity
20.
JAMA Otolaryngol Head Neck Surg ; 147(4): 404, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1086241
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