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1.
BMJ ; 376: e066871, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1707375

ABSTRACT

OBJECTIVES: To investigate the proportion of lateral flow tests (LFTs) that produce negative results in those with a high risk of infectiousness from SARS-CoV-2, to investigate the impact of the stage and severity of disease, and to compare predictions made by influential mathematical models with findings of empirical studies. DESIGN: Linked data analysis combining empirical evidence of the accuracy of the Innova LFT, the probability of positive viral culture or transmission to secondary cases, and the distribution of viral loads of SARS-CoV-2 in individuals in different settings. SETTING: Testing of individuals with symptoms attending NHS Test-and-Trace centres across the UK, residents without symptoms attending municipal mass testing centres in Liverpool, and students without symptoms screened at the University of Birmingham. PARTICIPANTS: Evidence for the sensitivity of the Innova LFT, based on 70 individuals with SARS-CoV-2 and LFT results. Infectiousness was based on viral culture rates on 246 samples (176 people with SARS-CoV-2) and secondary cases among 2 474 066 contacts; distributions of cycle threshold (Ct) values from 231 497 index individuals attending NHS Test-and-Trace centres; 70 people with SARS-CoV-2 detected in Liverpool and 62 people with SARS-CoV-2 in Birmingham (54 imputed). MAIN OUTCOME MEASURES: The predicted proportions who were missed by LFT and viral culture positive and missed by LFT and sources of secondary cases, in each of the three settings. Predictions were compared with those made by mathematical models. RESULTS: The analysis predicted that of those with a viral culture positive result, Innova would miss 20% attending an NHS Test-and-Trace centre, 29% without symptoms attending municipal mass testing, and 81% attending university screen testing without symptoms, along with 38%, 47%, and 90% of sources of secondary cases. In comparison, two mathematical models underestimated the numbers of missed infectious individuals (8%, 10%, and 32% in the three settings for one model, whereas the assumptions from the second model made it impossible to miss an infectious individual). Owing to the paucity of usable data, the inputs to the analyses are from limited sources. CONCLUSIONS: The proportion of infectious people with SARS-CoV-2 missed by LFTs is substantial enough to be of clinical importance. The proportion missed varied between settings because of different viral load distributions and is likely to be highest in those without symptoms. Key models have substantially overestimated the sensitivity of LFTs compared with empirical data. An urgent need exists for additional robust well designed and reported empirical studies from intended use settings to inform evidence based policy.


Subject(s)
COVID-19 Serological Testing/standards , COVID-19/epidemiology , Antibodies, Viral/blood , COVID-19/diagnosis , False Negative Reactions , False Positive Reactions , Humans , Pandemics , Reverse Transcriptase Polymerase Chain Reaction/standards , SARS-CoV-2 , Sensitivity and Specificity , Viral Load
2.
PLoS One ; 17(2): e0263736, 2022.
Article in English | MEDLINE | ID: covidwho-1674020

ABSTRACT

Sudden emergence and rapid spread of COVID-19 created an inevitable need for expansion of the COVID-19 laboratory testing network across the world. The strategy to test-track-treat was advocated for quick detection and containment of the disease. Being the second most populous country in the world, India was challenged to make COVID-19 testing available and accessible in all parts of the country. The molecular laboratory testing network was augmented expeditiously, and number of laboratories was increased from one in January 2020 to 2951 till mid-September, 2021. This rapid expansion warranted the need to have inbuilt systems of quality control/ quality assurance. In addition to the ongoing inter-laboratory quality control (ILQC), India implemented an External Quality Assurance Program (EQAP) with assistance from World Health Organization (WHO) and Royal College of Pathologists, Australasia. Out of the 953 open system rRTPCR laboratories in both public and private sector who participated in the first round of EQAP, 891(93.4%) laboratories obtained a passing score of > = 80%. The satisfactory performance of Indian COVID-19 testing laboratories has boosted the confidence of the public and policy makers in the quality of testing. ILQC and EQAP need to continue to ensure adherence of the testing laboratories to the desired quality standards.


Subject(s)
COVID-19 Testing/standards , COVID-19/diagnosis , Clinical Laboratory Techniques/standards , Laboratories/standards , Mass Screening/standards , Quality Assurance, Health Care/standards , Reverse Transcriptase Polymerase Chain Reaction/standards , COVID-19/epidemiology , COVID-19/genetics , COVID-19/virology , Humans , India/epidemiology , Quality Control , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Specimen Handling/methods
3.
APMIS ; 130(2): 95-100, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1511282

ABSTRACT

The aim was to determine the accuracy of anterior nasal swab in rapid antigen (Ag) tests in a low SARS-CoV-2 prevalence and massive screened community. Individuals, aged 18 years or older, who self-booked an appointment for real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test in March 2021 at a public test center in Copenhagen, Denmark were included. An oropharyngeal swab was collected for RT-PCR testing, followed by a swab from the anterior parts of the nose examined by Ag test (SD Biosensor). Accuracy of the Ag test was calculated with RT-PCR as reference. We included 7074 paired conclusive tests (n = 3461, female: 50.7%). The median age was 48 years (IQR: 36-57 years). The prevalence was 0.9%, that is, 66 tests were positive on RT-PCR. Thirty-two had a paired positive Ag test. The sensitivity was 48.5% and the specificity was 100%. This study conducted in a low prevalence setting in a massive screening set-up showed that the Ag test had a sensitivity of 48.5% and a specificity of 100%, that is, no false positive tests. The lower sensitivity is a challenge especially if Ag testing is not repeated frequently allowing this scalable test to be a robust supplement to RT-PCR testing in an ambitious public SARS-CoV-2 screening.


Subject(s)
COVID-19 Serological Testing/methods , COVID-19/diagnosis , Nose/virology , Reverse Transcriptase Polymerase Chain Reaction/methods , SARS-CoV-2/isolation & purification , Adult , Antigens, Viral/analysis , Antigens, Viral/immunology , COVID-19/virology , Female , Humans , Male , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction/standards , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Sensitivity and Specificity
4.
Pediatr Infect Dis J ; 40(11): e413-e417, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1447654

ABSTRACT

BACKGROUND: The viral dynamics and the role of children in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not completely understood. Our aim was to evaluate reverse transcription polymerase chain reaction (RT-PCR) cycle threshold (Ct) values among children with confirmed SARS-CoV-2 compared with that of adult subjects. METHODS: Patients (from 2 months to ≤18 years of age and adults) with signs and symptoms of acute SARS-CoV-2 infection for less than 7 days were prospectively enrolled in the study from May to November 2020. All participants performed RT-PCR assay for SARS-CoV-2 detection; Ct values of ORF1ab, N and S gene targets and the average of all the 3 probes were used as surrogates of viral load. RESULTS: There were 21 infants (2 months to <2 years), 40 children (≥2 to <12 years), 22 adolescents (≥12 to <18 years) and 293 adults of 376 participants with confirmed SARS-CoV-2 infections. RT-PCR Ct values from all participants less than 18 years of age, as well as from all childhood subgroups, were not significantly different from adults, comparing ORF1ab, N, S and all the gene targets together (P = 0.453). CONCLUSIONS: Ct values for children were comparable with that of adults. Although viral load is not the only determinant of SARS-CoV-2 transmission, children may play a role in the spread of coronavirus disease 2019 in the community.


Subject(s)
COVID-19 Testing , COVID-19/diagnosis , COVID-19/virology , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , Adolescent , Adult , Age Factors , Brazil , Child , Cross-Sectional Studies , Humans , Infant , RNA, Viral , Reverse Transcriptase Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/standards , Viral Load
5.
J Infect Dev Ctries ; 15(7): 913-917, 2021 07 31.
Article in English | MEDLINE | ID: covidwho-1339633

ABSTRACT

Early diagnosis is among the crucial measures to control the spread of SARS-CoV-2 infection. To date, reverse transcription polymerase chain reaction (RT-PCR) is the gold standard for COVID-19 testing, but various factors can affect its performance leading to false negative results. Hereby we present a patient with a high clinical suspicion for COVID-19 and had multiple negative RT-PCR results over 5 days. A 22-year-old woman presented with fever, dry cough, nausea, myalgia, headache, and mild dyspnea. Eleven days before, she was in close contact with her father who had tested positive for COVID-19. RT-PCR on nasopharyngeal and oropharyngeal swabs were performed on day 8, 9, and 12 of illness which all came back negative even after she started having a worsening dyspnea and showing an increased lung opacity from radiographic findings on day 11 of illness. Interestingly, her rapid antibody test (VivaDiag™ COVID-19 IgM/IgG rapid test by VivaChek Biotech (HangZhou,China) was positive for anti-SARS-CoV-2 Ig M and Ig G. Due to the worsening condition, she was referred to a tertiary hospital where her RT PCR result was positive on day 13 of illness. After 28 days from her first symptom, she was discharged from the hospital with improved symptoms and chest X-ray. As conclusions, in patients with high suspicion of COVID-19, repeat swab tests are mandatory if previous tests were negative. The diagnosis and treatment plan of COVID-19 should not solely be based on RT-PCR, but also consider the patient's history, symptoms, laboratory result, and radiographic findings.


Subject(s)
COVID-19 Nucleic Acid Testing/standards , COVID-19/diagnosis , Reverse Transcriptase Polymerase Chain Reaction/standards , SARS-CoV-2/genetics , Antibodies, Viral/blood , COVID-19/virology , False Negative Reactions , Female , Humans , Immunoglobulin M/blood , Nasopharynx/virology , Sensitivity and Specificity , Specimen Handling , Time Factors , Young Adult
6.
Przegl Epidemiol ; 75(1): 14-26, 2021.
Article in English | MEDLINE | ID: covidwho-1335556

ABSTRACT

INTRODUCTION: Since the SARS-CoV-2 emergence in 2019/2020, at least 158 million infections with this pathogen have been recorded, of which 3.29 million infected people have died. Due to the non-specific symptoms of SARS-CoV-2 infection, laboratory tests based on RT-PCR (reverse transcription and polymerase chain reaction) are mainly used in the diagnosis of COVID-19 disease. AIM: The aim of this study is to compare the molecular tests available on the Polish market for the diagnosis of SARS-CoV2 infection. RESULTS: Based on the data provided by the manufacturers and the performed laboratory analyses, we have shown that the available diagnostic kits differ mainly in the sensitivity and duration of the reaction. CONCLUSION: Due to the ongoing COVID-19 pandemic, the indicated parameters are key to effective control of the spread of SARS-CoV2, and therefore should be mainly taken into account when choosing and purchasing by diagnostic centres.


Subject(s)
COVID-19/diagnosis , Molecular Diagnostic Techniques/methods , Molecular Diagnostic Techniques/standards , Reverse Transcriptase Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/standards , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Viral Load , Humans , Poland , Sensitivity and Specificity
7.
Sci Rep ; 11(1): 14817, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1319044

ABSTRACT

A real-time reverse transcription polymerase chain reaction (RT-qPCR) assay that does not require Emergency Use Authorization (EUA) reagents was tested and validated for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the early stages of the outbreak of coronavirus disease 2019 (COVID-19) in the Republic of Korea. Early diagnosis of COVID-19 enables timely treatment and the implementation of public health measures. We validated the sensitivity, specificity, precision, linearity, accuracy, and robustness of the RT-qPCR assay for SARS-CoV-2 detection and compared its performance with that of several EUA-approved kits. Our RT-qPCR assay was highly specific for SARS-CoV-2 as demonstrated by not amplifying 13 other viruses that cause respiratory diseases. The assay showed high linearity using a viral isolate from a patient with known COVID-19 as well as plasmids containing target SARS-CoV-2 genes as templates. The assay showed good repeatability and reproducibility with a coefficient of variation of 3%, and a SARS-CoV-2 limit of detection of 1 PFU/mL. The RT-qPCR-based assay is highly effective and can facilitate the early diagnosis of COVID-19 without the use of EUA-approved kits or reagents in the Republic of Korea.


Subject(s)
COVID-19 Nucleic Acid Testing/methods , COVID-19/epidemiology , Real-Time Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/methods , Animals , COVID-19/virology , COVID-19 Nucleic Acid Testing/standards , Chlorocebus aethiops , Humans , Limit of Detection , Real-Time Polymerase Chain Reaction/standards , Reproducibility of Results , Republic of Korea , Reverse Transcriptase Polymerase Chain Reaction/standards , Vero Cells
8.
PLoS One ; 16(5): e0251214, 2021.
Article in English | MEDLINE | ID: covidwho-1215147

ABSTRACT

BACKGROUND: SARS-CoV-2 reinfection and reactivation has mostly been described in case reports. We therefore investigated the epidemiology of recurrent COVID-19 SARS-CoV-2. METHODS: Among patients testing positive for SARS-CoV-2 between March 11 and July 31, 2020 within an integrated healthcare system, we identified patients with a recurrent positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) assay ≥60 days after an initial positive test. To assign an overall likelihood of COVID-19 recurrence, we combined quantitative data from initial and recurrent positive RT-PCR cycle thresholds-a value inversely correlated with viral RNA burden- with a clinical recurrence likelihood assigned based on independent, standardized case review by two physicians. "Probable" or "possible" recurrence by clinical assessment was confirmed as the final recurrence likelihood only if a cycle threshold value obtained ≥60 days after initial testing was lower than its preceding cycle threshold or if the patient had an interval negative RT-PCR. RESULTS: Among 23,176 patients testing positive for SARS-CoV-2, 1,301 (5.6%) had at least one additional SARS-CoV-2 RT-PCRs assay ≥60 days later. Of 122 testing positive, 114 had sufficient data for evaluation. The median interval to the recurrent positive RT-PCR was 85.5 (IQR 74-107) days. After combining clinical and RT-PCR cycle threshold data, four patients (3.5%) met criteria for probable COVID-19 recurrence. All four exhibited symptoms at recurrence and three required a higher level of medical care compared to their initial diagnosis. After including six additional patients (5.3%) with possible recurrence, recurrence incidence was 4.3 (95% CI 2.1-7.9) cases per 10,000 COVID-19 patients. CONCLUSIONS: Only 0.04% of all COVID-19 patients in our health system experienced probable or possible recurrence; 90% of repeat positive SARS-CoV-2 RT-PCRs were not consistent with true recurrence. Our pragmatic approach combining clinical and quantitative RT-PCR data could aid assessment of COVID-19 reinfection or reactivation by clinicians and public health personnel.


Subject(s)
COVID-19/diagnosis , Adult , COVID-19/virology , COVID-19 Testing , Female , Humans , Male , Middle Aged , RNA, Viral/analysis , RNA, Viral/metabolism , Recurrence , Reverse Transcriptase Polymerase Chain Reaction/standards , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Time Factors , Viral Load
9.
J Comput Assist Tomogr ; 45(3): 485-489, 2021.
Article in English | MEDLINE | ID: covidwho-1165589

ABSTRACT

PURPOSE: The aim of this study was to study interreader agreement of the RSNA-STR-ACR (Radiological Society of North America/Society of Thoracic Radiology/American College of Radiology) consensus statement on reporting chest computed tomography (CT) findings related to COVID-19 on a sample of consecutive patients confirmed with reverse transcriptase-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus 2. MATERIALS AND METHODS: This institutional review board-approved retrospective study included 240 cases with a mean age of 47.6 ± 15.9 years, ranging from 20 to 90 years, who had a chest CT and RT-PCR performed. Computed tomography images were independently analyzed by 2 thoracic radiologists to identify patterns defined by the RSNA-STR-ACR consensus statement, and concordance was determined with weighted κ tests. Also, CT findings and CT severity scores were tabulated and compared. RESULTS: Of the 240 cases, 118 had findings on CT. The most frequent on the RT-PCR-positive group were areas of ground-glass opacities (80.5%), crazy-paving pattern (32.2%), and rounded pseudonodular ground-glass opacities (22.9%). Regarding the CT patterns, the most frequent in the RT-PCR-positive group was typical in 75.9%, followed by negative in 17.1%. The interreader agreement was 0.90 (95% confidence interval, 0.80-0.96) in this group. The CT severity score had a mean difference of -0.07 (95% confidence interval, -0.48 to 0.34) among the readers, showing no significant differences regarding visual estimation. CONCLUSIONS: The RSNA-STR-ACR consensus statement on reporting chest CT patterns for COVID-19 presents a high interreader agreement, with the typical pattern being more frequently associated with RT-PCR-positive examinations.


Subject(s)
COVID-19/diagnosis , Radiographic Image Interpretation, Computer-Assisted/standards , Reverse Transcriptase Polymerase Chain Reaction/standards , Tomography, X-Ray Computed/standards , Adult , Aged , Aged, 80 and over , Consensus , Female , Humans , Male , Middle Aged , Observer Variation , Retrospective Studies , Severity of Illness Index , Young Adult
10.
Pan Afr Med J ; 38: 68, 2021.
Article in English | MEDLINE | ID: covidwho-1154825

ABSTRACT

Efforts towards slowing down coronavirus (COVID-19) transmission and reducing mortality have focused on timely case detection, isolation and treatment. Availability of laboratory COVID-19 testing capacity using reverse-transcriptase polymerase chain reaction (RT-PCR) was essential for case detection. Hence, it was critical to establish and expand this capacity to test for COVID-19 in Ethiopia. To this end, using a three-phrased approach, potential public and private laboratories with RT-PCR technology were assessed, capacitated with trained human resource and equipped as required. These laboratories were verified to conduct COVID-19 testing with quality assurance checks regularly conducted. Within a 10-month period, COVID-19 testing laboratories increased from zero to 65 in all Regional States with the capacity to conduct 18,454 tests per day. The success of this rapid countrywide expansion of laboratory testing capacity for COVID-19 depended on some key operational implications: the strong laboratory coordination network within the country, the use of non-virologic laboratories, investment in capacity building, digitalization of the data for better information management and establishing quality assurance checks. A weak supply chain for laboratory reagents and consumables, differences in the brands of COVID-19 test kits, frequent breakdowns of the PCR machines and inadequate number of laboratory personnel following the adaption of a 24/7 work schedule were some of the challenges experienced during the process of laboratory expansion. Overall, we learn that multisectoral involvement of laboratories from non-health sectors, an effective supply chain system with an insight into the promotion of local production of laboratory supplies were critical during the laboratory expansion for COVID-19 testing. The consistent support from WHO and other implementing partners to Member States is needed in building the capacity of laboratories across different diagnostic capabilities in line with International Health Regulations. This will enable efficient adaptation to respond to future public health emergencies.


Subject(s)
COVID-19 Testing/methods , COVID-19/diagnosis , Laboratories/standards , Reverse Transcriptase Polymerase Chain Reaction/statistics & numerical data , COVID-19 Testing/standards , Capacity Building , Equipment and Supplies/statistics & numerical data , Ethiopia , Humans , Laboratories/statistics & numerical data , Molecular Diagnostic Techniques/methods , Molecular Diagnostic Techniques/standards , Quality Assurance, Health Care , Reverse Transcriptase Polymerase Chain Reaction/standards
11.
Cochrane Database Syst Rev ; 11: CD013787, 2020 11 19.
Article in English | MEDLINE | ID: covidwho-1047119

ABSTRACT

BACKGROUND: Specific diagnostic tests to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and resulting COVID-19 disease are not always available and take time to obtain results. Routine laboratory markers such as white blood cell count, measures of anticoagulation, C-reactive protein (CRP) and procalcitonin, are used to assess the clinical status of a patient. These laboratory tests may be useful for the triage of people with potential COVID-19 to prioritize them for different levels of treatment, especially in situations where time and resources are limited. OBJECTIVES: To assess the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. SEARCH METHODS: On 4 May 2020 we undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. SELECTION CRITERIA: We included both case-control designs and consecutive series of patients that assessed the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. The reference standard could be reverse transcriptase polymerase chain reaction (RT-PCR) alone; RT-PCR plus clinical expertise or and imaging; repeated RT-PCR several days apart or from different samples; WHO and other case definitions; and any other reference standard used by the study authors. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each included study. They also assessed the methodological quality of the studies, using QUADAS-2. We used the 'NLMIXED' procedure in SAS 9.4 for the hierarchical summary receiver operating characteristic (HSROC) meta-analyses of tests for which we included four or more studies. To facilitate interpretation of results, for each meta-analysis we estimated summary sensitivity at the points on the SROC curve that corresponded to the median and interquartile range boundaries of specificities in the included studies. MAIN RESULTS: We included 21 studies in this review, including 14,126 COVID-19 patients and 56,585 non-COVID-19 patients in total. Studies evaluated a total of 67 different laboratory tests. Although we were interested in the diagnotic accuracy of routine tests for COVID-19, the included studies used detection of SARS-CoV-2 infection through RT-PCR as reference standard. There was considerable heterogeneity between tests, threshold values and the settings in which they were applied. For some tests a positive result was defined as a decrease compared to normal vaues, for other tests a positive result was defined as an increase, and for some tests both increase and decrease may have indicated test positivity. None of the studies had either low risk of bias on all domains or low concerns for applicability for all domains. Only three of the tests evaluated had a summary sensitivity and specificity over 50%. These were: increase in interleukin-6, increase in C-reactive protein and lymphocyte count decrease. Blood count Eleven studies evaluated a decrease in white blood cell count, with a median specificity of 93% and a summary sensitivity of 25% (95% CI 8.0% to 27%; very low-certainty evidence). The 15 studies that evaluated an increase in white blood cell count had a lower median specificity and a lower corresponding sensitivity. Four studies evaluated a decrease in neutrophil count. Their median specificity was 93%, corresponding to a summary sensitivity of 10% (95% CI 1.0% to 56%; low-certainty evidence). The 11 studies that evaluated an increase in neutrophil count had a lower median specificity and a lower corresponding sensitivity. The summary sensitivity of an increase in neutrophil percentage (4 studies) was 59% (95% CI 1.0% to 100%) at median specificity (38%; very low-certainty evidence). The summary sensitivity of an increase in monocyte count (4 studies) was 13% (95% CI 6.0% to 26%) at median specificity (73%; very low-certainty evidence). The summary sensitivity of a decrease in lymphocyte count (13 studies) was 64% (95% CI 28% to 89%) at median specificity (53%; low-certainty evidence). Four studies that evaluated a decrease in lymphocyte percentage showed a lower median specificity and lower corresponding sensitivity. The summary sensitivity of a decrease in platelets (4 studies) was 19% (95% CI 10% to 32%) at median specificity (88%; low-certainty evidence). Liver function tests The summary sensitivity of an increase in alanine aminotransferase (9 studies) was 12% (95% CI 3% to 34%) at median specificity (92%; low-certainty evidence). The summary sensitivity of an increase in aspartate aminotransferase (7 studies) was 29% (95% CI 17% to 45%) at median specificity (81%) (low-certainty evidence). The summary sensitivity of a decrease in albumin (4 studies) was 21% (95% CI 3% to 67%) at median specificity (66%; low-certainty evidence). The summary sensitivity of an increase in total bilirubin (4 studies) was 12% (95% CI 3.0% to 34%) at median specificity (92%; very low-certainty evidence). Markers of inflammation The summary sensitivity of an increase in CRP (14 studies) was 66% (95% CI 55% to 75%) at median specificity (44%; very low-certainty evidence). The summary sensitivity of an increase in procalcitonin (6 studies) was 3% (95% CI 1% to 19%) at median specificity (86%; very low-certainty evidence). The summary sensitivity of an increase in IL-6 (four studies) was 73% (95% CI 36% to 93%) at median specificity (58%) (very low-certainty evidence). Other biomarkers The summary sensitivity of an increase in creatine kinase (5 studies) was 11% (95% CI 6% to 19%) at median specificity (94%) (low-certainty evidence). The summary sensitivity of an increase in serum creatinine (four studies) was 7% (95% CI 1% to 37%) at median specificity (91%; low-certainty evidence). The summary sensitivity of an increase in lactate dehydrogenase (4 studies) was 25% (95% CI 15% to 38%) at median specificity (72%; very low-certainty evidence). AUTHORS' CONCLUSIONS: Although these tests give an indication about the general health status of patients and some tests may be specific indicators for inflammatory processes, none of the tests we investigated are useful for accurately ruling in or ruling out COVID-19 on their own. Studies were done in specific hospitalized populations, and future studies should consider non-hospital settings to evaluate how these tests would perform in people with milder symptoms.


Subject(s)
COVID-19 Testing/methods , COVID-19/diagnosis , Diagnostic Tests, Routine/methods , SARS-CoV-2/isolation & purification , Bias , Biomarkers/blood , C-Reactive Protein/analysis , COVID-19/blood , COVID-19/epidemiology , COVID-19 Testing/standards , Creatine Kinase/blood , Creatinine/blood , Diagnostic Tests, Routine/standards , Humans , Interleukin-6/blood , L-Lactate Dehydrogenase/blood , Leukocyte Count , Liver Function Tests , Lymphocyte Count , Pandemics , Platelet Count , ROC Curve , Reference Values , Reverse Transcriptase Polymerase Chain Reaction/standards , Sensitivity and Specificity , Triage
12.
Indian J Med Microbiol ; 39(1): 133-135, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1009582

ABSTRACT

In the modern COVID-19 pandemic, reverse transcription-polymerase chain reaction (RT-PCR) positivity has a major role in the diagnosis of the disease. However, in deciding the patient's discharge or de-isolation, its role is still debatable. We are, hereby, describing three cases (an intern, a nursing officer and a caretaker of another patient) where only RT-PCR could not help much since it was persistently positive for >20 days of the illness course. Instead, the cycle threshold (Ct) values could have better correlated with the infectivity of COVID. We propose a rising trend (24 h apart) and absolute Ct value > 25, instead of RT-PCR negativity (which was taken as Ct value > 36 in our laboratory), to be used in deciding the infective potential of the patients, their discharge from the hospital and de-isolation of the patients. This will help in the timely discharge of patients from health-care institutions and home isolation, which, as a result, will lead to optimal utilisation of the limited hospital resources we have available in the line of the ongoing pandemic. Future studies are required to define the exact cut-off of Ct value for de-isolation purposes.


Subject(s)
COVID-19/diagnosis , COVID-19/virology , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , Adult , COVID-19/epidemiology , Disease Management , Female , Hospitalization , Humans , Male , Reverse Transcriptase Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/standards , SARS-CoV-2/isolation & purification , Severity of Illness Index , Symptom Assessment , Young Adult
13.
Cochrane Database Syst Rev ; 6: CD013652, 2020 06 25.
Article in English | MEDLINE | ID: covidwho-981322

ABSTRACT

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and resulting COVID-19 pandemic present important diagnostic challenges. Several diagnostic strategies are available to identify current infection, rule out infection, identify people in need of care escalation, or to test for past infection and immune response. Serology tests to detect the presence of antibodies to SARS-CoV-2 aim to identify previous SARS-CoV-2 infection, and may help to confirm the presence of current infection. OBJECTIVES: To assess the diagnostic accuracy of antibody tests to determine if a person presenting in the community or in primary or secondary care has SARS-CoV-2 infection, or has previously had SARS-CoV-2 infection, and the accuracy of antibody tests for use in seroprevalence surveys. SEARCH METHODS: We undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. We conducted searches for this review iteration up to 27 April 2020. SELECTION CRITERIA: We included test accuracy studies of any design that evaluated antibody tests (including enzyme-linked immunosorbent assays, chemiluminescence immunoassays, and lateral flow assays) in people suspected of current or previous SARS-CoV-2 infection, or where tests were used to screen for infection. We also included studies of people either known to have, or not to have SARS-CoV-2 infection. We included all reference standards to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction tests (RT-PCR) and clinical diagnostic criteria). DATA COLLECTION AND ANALYSIS: We assessed possible bias and applicability of the studies using the QUADAS-2 tool. We extracted 2x2 contingency table data and present sensitivity and specificity for each antibody (or combination of antibodies) using paired forest plots. We pooled data using random-effects logistic regression where appropriate, stratifying by time since post-symptom onset. We tabulated available data by test manufacturer. We have presented uncertainty in estimates of sensitivity and specificity using 95% confidence intervals (CIs). MAIN RESULTS: We included 57 publications reporting on a total of 54 study cohorts with 15,976 samples, of which 8526 were from cases of SARS-CoV-2 infection. Studies were conducted in Asia (n = 38), Europe (n = 15), and the USA and China (n = 1). We identified data from 25 commercial tests and numerous in-house assays, a small fraction of the 279 antibody assays listed by the Foundation for Innovative Diagnostics. More than half (n = 28) of the studies included were only available as preprints. We had concerns about risk of bias and applicability. Common issues were use of multi-group designs (n = 29), inclusion of only COVID-19 cases (n = 19), lack of blinding of the index test (n = 49) and reference standard (n = 29), differential verification (n = 22), and the lack of clarity about participant numbers, characteristics and study exclusions (n = 47). Most studies (n = 44) only included people hospitalised due to suspected or confirmed COVID-19 infection. There were no studies exclusively in asymptomatic participants. Two-thirds of the studies (n = 33) defined COVID-19 cases based on RT-PCR results alone, ignoring the potential for false-negative RT-PCR results. We observed evidence of selective publication of study findings through omission of the identity of tests (n = 5). We observed substantial heterogeneity in sensitivities of IgA, IgM and IgG antibodies, or combinations thereof, for results aggregated across different time periods post-symptom onset (range 0% to 100% for all target antibodies). We thus based the main results of the review on the 38 studies that stratified results by time since symptom onset. The numbers of individuals contributing data within each study each week are small and are usually not based on tracking the same groups of patients over time. Pooled results for IgG, IgM, IgA, total antibodies and IgG/IgM all showed low sensitivity during the first week since onset of symptoms (all less than 30.1%), rising in the second week and reaching their highest values in the third week. The combination of IgG/IgM had a sensitivity of 30.1% (95% CI 21.4 to 40.7) for 1 to 7 days, 72.2% (95% CI 63.5 to 79.5) for 8 to 14 days, 91.4% (95% CI 87.0 to 94.4) for 15 to 21 days. Estimates of accuracy beyond three weeks are based on smaller sample sizes and fewer studies. For 21 to 35 days, pooled sensitivities for IgG/IgM were 96.0% (95% CI 90.6 to 98.3). There are insufficient studies to estimate sensitivity of tests beyond 35 days post-symptom onset. Summary specificities (provided in 35 studies) exceeded 98% for all target antibodies with confidence intervals no more than 2 percentage points wide. False-positive results were more common where COVID-19 had been suspected and ruled out, but numbers were small and the difference was within the range expected by chance. Assuming a prevalence of 50%, a value considered possible in healthcare workers who have suffered respiratory symptoms, we would anticipate that 43 (28 to 65) would be missed and 7 (3 to 14) would be falsely positive in 1000 people undergoing IgG/IgM testing at days 15 to 21 post-symptom onset. At a prevalence of 20%, a likely value in surveys in high-risk settings, 17 (11 to 26) would be missed per 1000 people tested and 10 (5 to 22) would be falsely positive. At a lower prevalence of 5%, a likely value in national surveys, 4 (3 to 7) would be missed per 1000 tested, and 12 (6 to 27) would be falsely positive. Analyses showed small differences in sensitivity between assay type, but methodological concerns and sparse data prevent comparisons between test brands. AUTHORS' CONCLUSIONS: The sensitivity of antibody tests is too low in the first week since symptom onset to have a primary role for the diagnosis of COVID-19, but they may still have a role complementing other testing in individuals presenting later, when RT-PCR tests are negative, or are not done. Antibody tests are likely to have a useful role for detecting previous SARS-CoV-2 infection if used 15 or more days after the onset of symptoms. However, the duration of antibody rises is currently unknown, and we found very little data beyond 35 days post-symptom onset. We are therefore uncertain about the utility of these tests for seroprevalence surveys for public health management purposes. Concerns about high risk of bias and applicability make it likely that the accuracy of tests when used in clinical care will be lower than reported in the included studies. Sensitivity has mainly been evaluated in hospitalised patients, so it is unclear whether the tests are able to detect lower antibody levels likely seen with milder and asymptomatic COVID-19 disease. The design, execution and reporting of studies of the accuracy of COVID-19 tests requires considerable improvement. Studies must report data on sensitivity disaggregated by time since onset of symptoms. COVID-19-positive cases who are RT-PCR-negative should be included as well as those confirmed RT-PCR, in accordance with the World Health Organization (WHO) and China National Health Commission of the People's Republic of China (CDC) case definitions. We were only able to obtain data from a small proportion of available tests, and action is needed to ensure that all results of test evaluations are available in the public domain to prevent selective reporting. This is a fast-moving field and we plan ongoing updates of this living systematic review.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Antibody Specificity , COVID-19 , Coronavirus Infections/epidemiology , False Negative Reactions , False Positive Reactions , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Immunoglobulin M/blood , Pandemics , Pneumonia, Viral/epidemiology , Reference Standards , Reverse Transcriptase Polymerase Chain Reaction/standards , Reverse Transcriptase Polymerase Chain Reaction/statistics & numerical data , SARS-CoV-2 , Selection Bias , Sensitivity and Specificity , Serologic Tests/methods , Serologic Tests/standards
14.
Rev Med Virol ; 31(3): e2181, 2021 05.
Article in English | MEDLINE | ID: covidwho-909129

ABSTRACT

This study aimed to assess the diagnostic test accuracy (DTA) of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) serological test methods and the kinetics of antibody positivity. Systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. We included articles evaluating the diagnostic accuracy of serological tests and the kinetics of antibody positivity. MEDLINE through PubMed, Scopus, medRxiv and bioRxiv were sources of articles. Methodological qualities of included articles were appraised using QUADAS-2 while Metandi performs bivariate meta-analysis of DTA using a generalized linear mixed-model approach. Stata 14 and Review Manager 5.3 were used for data analysis. The summary sensitivity/specificity of chemiluminescence immunoassay (CLIA), enzyme-linked immunosorbent assay (ELISA) and lateral flow immunoassay (LFIA) were 92% (95% CI: 86%-95%)/99% (CI: 97%-99%), 86% (CI: 82%-89%)/99% (CI: 98%-100%) and 78% (CI: 71%-83%)/98% (95% CI: 96%-99%), respectively. Moreover, CLIA-based assays produced nearly 100% sensitivity within 11-15 days post-symptom onset (DPSO). Based on antibody type, the sensitivity of ELISA-total antibody, CLIA-IgM/G and CLIA-IgG gauged at 94%, 92% and 92%, respectively. The sensitivity of CLIA-RBD assay reached 96%, while LFIA-S demonstrated the lowest sensitivity, 71% (95% CI: 58%-80%). CLIA assays targeting antibodies against RBD considered the best DTA. The antibody positivity rate increased corresponding with DPSO, but there was some decrement when moving from acute phase to convalescent phase of infection. As immunoglobulin isotope-related DTA was heterogeneous, our data have insufficient evidence to recommend CLIA/ELISA for clinical decision-making, but likely to have comparative advantage over RT-qPCR in certain circumstances and geographic regions.


Subject(s)
COVID-19 Serological Testing/standards , COVID-19/diagnosis , Enzyme-Linked Immunosorbent Assay/standards , Flow Cytometry/standards , Luminescent Measurements/standards , SARS-CoV-2/pathogenicity , Antibodies, Viral/blood , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , COVID-19 Serological Testing/methods , Convalescence , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , RNA, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction/standards , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Sensitivity and Specificity , Severity of Illness Index
15.
BMC Med ; 18(1): 346, 2020 11 04.
Article in English | MEDLINE | ID: covidwho-908264

ABSTRACT

BACKGROUND: Tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral ribonucleic acid (RNA) using reverse transcription polymerase chain reaction (RT-PCR) are pivotal to detecting current coronavirus disease (COVID-19) and duration of detectable virus indicating potential for infectivity. METHODS: We conducted an individual participant data (IPD) systematic review of longitudinal studies of RT-PCR test results in symptomatic SARS-CoV-2. We searched PubMed, LitCOVID, medRxiv, and COVID-19 Living Evidence databases. We assessed risk of bias using a QUADAS-2 adaptation. Outcomes were the percentage of positive test results by time and the duration of detectable virus, by anatomical sampling sites. RESULTS: Of 5078 studies screened, we included 32 studies with 1023 SARS-CoV-2 infected participants and 1619 test results, from - 6 to 66 days post-symptom onset and hospitalisation. The highest percentage virus detection was from nasopharyngeal sampling between 0 and 4 days post-symptom onset at 89% (95% confidence interval (CI) 83 to 93) dropping to 54% (95% CI 47 to 61) after 10 to 14 days. On average, duration of detectable virus was longer with lower respiratory tract (LRT) sampling than upper respiratory tract (URT). Duration of faecal and respiratory tract virus detection varied greatly within individual participants. In some participants, virus was still detectable at 46 days post-symptom onset. CONCLUSIONS: RT-PCR misses detection of people with SARS-CoV-2 infection; early sampling minimises false negative diagnoses. Beyond 10 days post-symptom onset, lower RT or faecal testing may be preferred sampling sites. The included studies are open to substantial risk of bias, so the positivity rates are probably overestimated.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Reverse Transcriptase Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/standards , Betacoronavirus/genetics , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques , Coronavirus Infections/genetics , Humans , Longitudinal Studies , Pandemics , Pneumonia, Viral/genetics , SARS-CoV-2
16.
Sci Rep ; 10(1): 18899, 2020 11 03.
Article in English | MEDLINE | ID: covidwho-908050

ABSTRACT

Severe acute respiratory coronavirus 2 (SARS-CoV-2) testing reagents are expected to become scarce worldwide. However, little is known regarding whether pooling of samples accurately detects SARS-CoV-2. To validate the feasibility of pooling samples, serial dilution analysis and spike-in experiments were conducted using synthetic DNA and nucleic acids extracted from SARS-CoV-2-positive and -negative patients. Furthermore, we studied 1000 individuals, 667 of whom were "healthy" individuals (195 healthcare workers and 472 hospitalized patients with disorders other than COVID-19 infection), and 333 infection-suspected patients with cough and fever. Serial dilution analysis showed a limit of detection of around 10-100 viral genome copies according to the protocol of the National Institute of Infectious Diseases, Japan. Spike-in experiments demonstrated that RT-qPCR detected positive signals in pooled samples with SARS-CoV-2-negative and -positive patients at 5-, 10-, 20-fold dilutions. By screening with this pooling strategy, by the end of April 2020 there were 12 SARS-CoV-2-positive patients in 333 infection-suspected patients (3.6%) and zero in 667 "healthy" controls. We obtained these results with a total of 538 runs using the pooling strategy, compared with 1000 standard runs. In a prospective study, we successfully detected SARS-CoV-2 using 10- to 20-fold diluted samples of nasopharyngeal swabs from eighteen COVID-19 patients with wide ranges of viral load. Pooling sample is feasible for conserving test reagents and detecting SARS-CoV-2 in clinical settings. This strategy will help us to research the prevalence infected individuals and provide infected-status information to prevent the spread of the virus and nosocomial transmission.


Subject(s)
Clinical Laboratory Techniques/methods , Mass Screening/methods , Reverse Transcriptase Polymerase Chain Reaction/methods , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , COVID-19 Testing , Clinical Laboratory Techniques/standards , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Humans , Limit of Detection , Mass Screening/standards , Reproducibility of Results , Respiratory Mucosa/virology , Reverse Transcriptase Polymerase Chain Reaction/standards , SARS-CoV-2
17.
Genes (Basel) ; 11(10)2020 10 12.
Article in English | MEDLINE | ID: covidwho-905037

ABSTRACT

WHO declared the novel coronavirus (COVID-19) outbreak a global pandemic on 11 March 2020. The establishment of standardized RT-qPCR protocols for respiratory secretions testing, as well as sharing of specimens, data, and information became critical. Here, we investigate the analytical performance of two interim RT-qPCR protocols (Charité and Centers for Disease Control (CDC)) for the qualitative detection of SARS-CoV-2 executed in a fully automated platform. Analytical specificity, PCR amplification efficiency, analytical sensitivity (limit of detection), and cross-reactivity were evaluated using contrived samples. The on-going accuracy was evaluated by retrospective analysis of our test results database (real clinical samples). N1, E, and a modified version of RdRP assays presented adequate analytical specificity, amplification efficiency, and analytical sensitivity using contrived samples. The three assays were applied to all individuals who requested the SARS-CoV-2 molecular test assay in our laboratory and it was observed that N1 gave more positive results than E, and E gave more positive results than RdRP (modified). The RdRP and E were removed from the test and its final version, based on N1 assay only, was applied to 30,699 Brazilian individuals (from 19 February 2020 to 8 May 2020). The aggregated test results available in the database were also presented.


Subject(s)
Automation, Laboratory/standards , Clinical Laboratory Techniques/standards , Real-Time Polymerase Chain Reaction/standards , Reverse Transcriptase Polymerase Chain Reaction/standards , Automation, Laboratory/methods , COVID-19 Testing , COVID-19 Vaccines , Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Humans , Limit of Detection , Real-Time Polymerase Chain Reaction/methods , Reproducibility of Results , Reverse Transcriptase Polymerase Chain Reaction/methods
18.
PLoS Biol ; 18(10): e3000867, 2020 10.
Article in English | MEDLINE | ID: covidwho-901993

ABSTRACT

The current quantitative reverse transcription PCR (RT-qPCR) assay recommended for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing in the United States requires analysis of 3 genomic targets per sample: 2 viral and 1 host. To simplify testing and reduce the volume of required reagents, we devised a multiplex RT-qPCR assay to detect SARS-CoV-2 in a single reaction. We used existing N1, N2, and RP primer and probe sets by the Centers for Disease Control and Prevention, but substituted fluorophores to allow multiplexing of the assay. The cycle threshold (Ct) values of our multiplex RT-qPCR were comparable to those obtained by the single assay adapted for research purposes. Low copy numbers (≥500 copies/reaction) of SARS-CoV-2 RNA were consistently detected by the multiplex RT-qPCR. Our novel multiplex RT-qPCR improves upon current single diagnostics by saving reagents, costs, time, and labor.


Subject(s)
Betacoronavirus/genetics , Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Multiplex Polymerase Chain Reaction/standards , Pneumonia, Viral/diagnosis , RNA, Viral/genetics , Reagent Kits, Diagnostic/standards , Reverse Transcriptase Polymerase Chain Reaction/standards , Betacoronavirus/pathogenicity , COVID-19 , COVID-19 Testing , Case-Control Studies , Clinical Laboratory Techniques/standards , Coronavirus Infections/virology , DNA Primers/standards , HEK293 Cells , Humans , Limit of Detection , Nasopharynx/virology , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , United States
19.
Euro Surveill ; 25(27)2020 07.
Article in English | MEDLINE | ID: covidwho-845124

ABSTRACT

Laboratory preparedness with quality-assured diagnostic assays is essential for controlling the current coronavirus disease (COVID-19) outbreak. We conducted an external quality assessment study with inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) samples to support clinical laboratories with a proficiency testing option for molecular assays. To analyse SARS-CoV-2 testing performance, we used an online questionnaire developed for the European Union project RECOVER to assess molecular testing capacities in clinical diagnostic laboratories.


Subject(s)
Clinical Laboratory Techniques/methods , Clinical Laboratory Techniques/standards , Coronavirus Infections/diagnosis , Coronavirus/isolation & purification , Molecular Diagnostic Techniques/methods , Pandemics , Pneumonia, Viral/diagnosis , Betacoronavirus , COVID-19 , COVID-19 Testing , COVID-19 Vaccines , Clinical Laboratory Services , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Disease Outbreaks , Europe , Humans , Pandemics/prevention & control , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Real-Time Polymerase Chain Reaction/standards , Reverse Transcriptase Polymerase Chain Reaction/standards , SARS-CoV-2 , Sensitivity and Specificity , Surveys and Questionnaires
20.
Clin Chim Acta ; 511: 143-148, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-844315

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) has become a pandemic. Reverse transcription quantitative PCR (RT-qPCR) has played a vital role in the diagnosis of COVID-19, but the rates of false negatives is not ideal in dealing with this highly infectious virus. It is thus necessary to systematically evaluate the clinical performance of the single-, dual-, triple-target detection kits to guide the clinical diagnosis of this disease. METHODS: A series of reference materials calibrated by droplet digital PCR (ddPCR) and 57 clinical samples were used to evaluate the clinical performance of six single-, dual-, triple-target SARS-CoV-2 nucleic acid detection kits based on RT-qPCR. RESULTS: The dual-target kits, kit B and kit C had the highest and the lowest detection sensitivity, which was 125 copies/mL and 4000 copies/mL, respectively. Among the 57 clinical samples from patients with COVID-19, 47 were tested positive by the kit B, while 35, 29, 28, 30, and 29 were found positive by the kits A, C, D, E, and F, respectively. The number of targets in a detection kit is not a key factor affecting sensitivity, while the amount of sample loading may influence the performance of a detection kit. CONCLUSIONS: This study provides a guide when choosing or developing a nucleic acid detection kit for the diagnosis of COVID-19. Also, the absolute-quantification feature and high-sensitivity performance of ddPCR, suggesting that it can be used to review clinically suspected samples.


Subject(s)
COVID-19/diagnosis , COVID-19/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/standards , SARS-CoV-2/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Humans , Male , Middle Aged , Reverse Transcription/genetics , SARS-CoV-2/isolation & purification , Young Adult
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