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      Diagnostic accuracy of serological tests for covid-19: systematic review and meta-analysis

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          To determine the diagnostic accuracy of serological tests for coronavirus disease-2019 (covid-19).


          Systematic review and meta-analysis.

          Data sources

          Medline, bioRxiv, and medRxiv from 1 January to 30 April 2020, using subject headings or subheadings combined with text words for the concepts of covid-19 and serological tests for covid-19.

          Eligibility criteria and data analysis

          Eligible studies measured sensitivity or specificity, or both of a covid-19 serological test compared with a reference standard of viral culture or reverse transcriptase polymerase chain reaction. Studies were excluded with fewer than five participants or samples. Risk of bias was assessed using quality assessment of diagnostic accuracy studies 2 (QUADAS-2). Pooled sensitivity and specificity were estimated using random effects bivariate meta-analyses.

          Main outcome measures

          The primary outcome was overall sensitivity and specificity, stratified by method of serological testing (enzyme linked immunosorbent assays (ELISAs), lateral flow immunoassays (LFIAs), or chemiluminescent immunoassays (CLIAs)) and immunoglobulin class (IgG, IgM, or both). Secondary outcomes were stratum specific sensitivity and specificity within subgroups defined by study or participant characteristics, including time since symptom onset.


          5016 references were identified and 40 studies included. 49 risk of bias assessments were carried out (one for each population and method evaluated). High risk of patient selection bias was found in 98% (48/49) of assessments and high or unclear risk of bias from performance or interpretation of the serological test in 73% (36/49). Only 10% (4/40) of studies included outpatients. Only two studies evaluated tests at the point of care. For each method of testing, pooled sensitivity and specificity were not associated with the immunoglobulin class measured. The pooled sensitivity of ELISAs measuring IgG or IgM was 84.3% (95% confidence interval 75.6% to 90.9%), of LFIAs was 66.0% (49.3% to 79.3%), and of CLIAs was 97.8% (46.2% to 100%). In all analyses, pooled sensitivity was lower for LFIAs, the potential point-of-care method. Pooled specificities ranged from 96.6% to 99.7%. Of the samples used for estimating specificity, 83% (10 465/12 547) were from populations tested before the epidemic or not suspected of having covid-19. Among LFIAs, pooled sensitivity of commercial kits (65.0%, 49.0% to 78.2%) was lower than that of non-commercial tests (88.2%, 83.6% to 91.3%). Heterogeneity was seen in all analyses. Sensitivity was higher at least three weeks after symptom onset (ranging from 69.9% to 98.9%) compared with within the first week (from 13.4% to 50.3%).


          Higher quality clinical studies assessing the diagnostic accuracy of serological tests for covid-19 are urgently needed. Currently, available evidence does not support the continued use of existing point-of-care serological tests.

          Study registration

          PROSPERO CRD42020179452.

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          Most cited references 25

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          Diagnostic value and dynamic variance of serum antibody in coronavirus disease 2019

          Highlights • Viral serological testing is an effective means of diagnosis for SARS-CoV-2 infection. • The positive rate and titer variance of serum IgG were found to be higher than those of IgM in the course of COVID-19. • The median titer of IgG after a virus-negative result was double that before becoming negative.
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            Performance of VivaDiag COVID‐19 IgM/IgG Rapid Test is inadequate for diagnosis of COVID‐19 in acute patients referring to emergency room department

            To the Editor, From late December 2019, coronavirus infectious disease (COVID‐19) epidemics spread from Wuhan, China, to all over the world, including Italy. 1 , 2 , 3 To date, real‐time reverse transcription‐polymerase chain reaction (RT‐PCR) in respiratory samples is the current gold standard method for the diagnosis of COVID‐19. 4 , 5 However, molecular testings are time consuming and require specialized operators, factors that limit their use in real life when the rapid diagnosis is required for fast intervention decisions. Recently, an easy to perform serological assay has been assessed 6 to differentiate COVID‐19 positive patients from negative subjects. We herein report results of a real‐life study performed in an emergency room department of a tertiary hospital in Northern Italy to validate VivaDiag COVID‐19 IgM/IgG Rapid Test lateral flow immunoassay (LFIA) for the rapid diagnosis of COVID‐19. Overall 110 subjects were tested for COVID‐19‐specific serological assay at Fondazione IRCCS Policlinico San Matteo. In detail, we enrolled 30 healthy volunteers with documented negative results for COVID‐19 RT‐PCR in respiratory samples (M 11/F 19; median age, 38.5; range, 25‐69 years). Ten of them (33.3%) had been infected in the past with one of the common OC43, 229E, HKU1, and NL63 coronavirus. Thirty COVID‐19‐positive patients (25 M/5 F; median age, 73.5; range, 38‐86 years) admitted to the Infectious Diseases Department or at the Intensive Care Unit were tested as positive controls. Finally, the performance of VivaDiag COVID‐19 IgM/IgG Rapid Test LFIA was tested in 50 patients at their first access at emergency room department with fever and respiratory syndrome (34 M/16 F; median age, 61.50; range, 33‐97 years) in comparison with results of nasal swab molecular screening. 5 VivaDiag COVID‐19 IgM/IgG from VivaChek was performed according to manufacturer's instruction by adding 10 µL of serum or whole blood sample into the sample port followed by adding 2 to 3 drops (70‐100 µL) of dilution buffer. 6 After about 15 minutes, results were read. Respiratory samples (FLOQSwabs; Copan Italia, Brescia, Italy) were collected from all the patients. Total nucleic acids (DNA/RNA) were extracted from 200 µL of UTM using the QIAsymphony instrument with QIAsymphony DSP Virus/Pathogen Midi Kit (complex 400 protocols) according to the manufacturer's instructions (QIAGEN; Qiagen, Hilden, Germany). Specific real‐time RT‐PCR targeting RNA‐dependent RNA polymerase and E genes were used to detect the presence of SARS‐CoV‐2 according to the WHO guidelines 7 and Corman et al 5 protocols. In the cohort of patients admitted to the emergency room department, data from serological tests were compared to molecular results to define specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) of the rapid serological test. As expected, all 30 COVID‐19 negative volunteers were negative for both immunoglobulin G (IgG) and immunoglobulin M (IgM) using the VivaDiag COVID‐19 IgM/IgG Rapid Test. No cross‐reactivity was detected in the 10 subjects with previous coronaviruses infection, supporting the high specificity of the VivaDiag COVID‐19 IgM/IgG Rapid Test LFIA. Serum samples were obtained at a median 7 days (interquartile range, 4‐11) after the first COVID‐19 positive result from 30 hospitalized patients. A total of 19 of 30 (63.3%) were positive for both IgM and IgG, 5 of 30 (16.7%) were negative for both IgG and IgM, 5 of 30 (16.7%) were weakly positive for both IgM and IgG, and only 1 of 30 (3.3%) was positive for IgM and negative for IgG. Thus, the sensitivity of the rapid assay was suboptimal (data not are shown). A possible explanation is the low antibody titers or a delayed humoral response. 6 Focusing on acute patients enrolled from the emergency room department, 12 of 50 (24%) were negative for COVID‐19 by real‐time RT‐PCR. Of these, 1 (8.3%) showed a positive results for the VivaDiag COVID‐19 IgM/IgG Rapid Test, while the other 11 of 12 (91.7%) tested negative. On the other side, 38 patients were positive for COVID‐19 by real‐time RT‐PCR. Of these, only 7 (18.4%) showed a positive or weak positive serology for IgM and/or IgG, while the other 31 of 38 (81.6%) tested negative for the rapid serology assay (Table 1). Thus, the sensitivity of the VivaDiag COVID‐19 IgM/IgG Rapid Test was 18.4%, specificity was 91.7%, while NPV was 26.2%, and PPV was 87.5% in patients enrolled from emergency room department. In contrast with the high levels of sensitivity reported in the previous study, 6 VivaDiag COVID‐19 IgM/IgG Rapid Test revealed a very poor sensitivity (less than 20%). Indeed, the majority of patients that tested positive for COVID‐19 by real‐time RT‐PCR would have been identified as negative using only the rapid serological assay, leading to a misdiagnosis of COVID‐19 disease in the vast majority of patients. On the basis of our results, VivaDiag COVID‐19 IgM/IgG Rapid Test LFIA is not recommended for triage of patients with suspected COVID‐19. Table 1 Characteristics and VivaDiag COVID‐19 IgM/IgG Rapid Test results of 50 consecutive patients referred to the emergency room department Patient Sex Age Result of COVID‐19 real‐time RT‐PCR on NS VivaDiag COVID‐19 IgM/IgG Rapid Test IgM IgG 1 M 33 neg − − 2 M 51 pos − − 3 M 51 pos − − 4 M 38 pos − − 5 F 80 pos − − 6 F 64 neg − − 7 M 81 neg − − 8 M 76 pos +/− − 9 M 33 pos − − 10 M 37 neg − − 11 F 45 pos − − 12 M 53 pos − − 13 M 66 neg − − 14 M 78 pos − − 15 F 97 pos − − 16 M 38 pos − − 17 M 72 pos − − 18 M 56 pos − − 19 M 80 pos − +/− 20 M 72 pos − − 21 F 55 pos − − 22 M 82 pos − − 23 M 47 pos + +/− 24 F 63 pos − − 25 F 80 pos +/− − 26 M 59 pos − − 27 M 66 pos − − 28 M 39 pos − − 29 F 78 neg − − 30 M 71 neg − − 31 F 46 neg − − 32 F 51 pos − − 33 F 75 pos − − 34 F 82 pos + +/− 35 F 51 pos +/− +/− 36 M 84 pos − − 37 M 50 pos − − 38 M 50 pos + +/− 39 F 72 neg − − 40 M 54 neg − − 41 F 64 neg + − 42 M 64 pos − − 43 M 70 pos − − 44 M 56 pos − − 45 M 68 pos − − 46 F 36 pos − − 47 M 60 pos − − 48 M 66 pos − − 49 M 54 neg − − 50 M 56 pos − − Abbreviations: −, negative result; +, positive result; +/−, weakly positive result; COVID‐19, coronavirus infectious disease 2019; IgG, immunoglobulin G; IgM, immunoglobulin M; NS, nasopharyngeal swab; RT‐PCR, reverse transcription‐polymerase chain reaction. John Wiley & Sons, Ltd. This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency. MEMBERS OF THE SAN MATTEO PAVIA COVID‐19 TASK FORCE R. Bruno, M. Mondelli, E. Brunetti, A. Di Matteo, E. Seminari, L. Maiocchi, V. Zuccaro, L. Pagnucco, B. Mariani, S. Ludovisi, R. Lissandrin, A. Parisi, P. Sacchi, S. F. A. Patruno, G. Michelone, R. Gulminetti, D. Zanaboni, S. Novati, R. Maserati, P. Orsolini, and M. Vecchia (ID Staff); M. Sciarra, E. Asperges, M. Colaneri, A. Di Filippo, M. Sambo, S. Biscarini, M. Lupi, S. Roda, T. C. Pieri, I. Gallazzi, M. Sachs, and P. Valsecchi (ID Resident); S. Perlini, C. Alfano, M. Bonzano, F. Briganti, G. Crescenzi, A. G. Falchi, R. Guarnone, B. Guglielmana, E. Maggi, I. Martino, P. Pettenazza, S. Pioli di Marco, F. Quaglia, A. Sabena, F. Salinaro, F. Speciale, and I. Zunino (ECU Staff Emergency Care Unit); M. De Lorenzo, G. Secco, L. Dimitry, G. Cappa, I. Maisak, B. Chiodi, M. Sciarrini, B. Barcella, F. Resta, L. Moroni, G. Vezzoni, L. Scattaglia, E. Boscolo, C. Zattera, M. F. Tassi, V. Capozza, D. Vignaroli, and M. Bazzini (ECU Resident Emergency Care Unit); G. Iotti, F. Mojoli, M. Belliato, L. Perotti, S. Mongodi, and G. Tavazzi (Intensive Care Unit); G. Marseglia, A. Licari, and I. Brambilla (Pediatric Unit); D. Barbarini, A. Bruno, P. Cambieri, G. Campanini, G. Comolli, M. Corbella, R. Daturi, M. Furione, B. Mariani, R. Maserati, E. Monzillo, S. Paolucci, M. Parea, E. Percivalle, A. Piralla, F. Rovida, A. Sarasini, and M. Zavattoni (Virology Staff); G. Adzasehoun, L. Bellotti, E. Cabano, G. Casali, L. Dossena, G. Frisco, G. Garbagnoli, A. Girello, V. Landini, C. Lucchelli, V. Maliardi, S. Pezzaia, and M. Premoli (Virology Technical staff); A. Bonetti, G. Caneva, I. Cassaniti, A. Corcione, R. Di Martino, A. Di Napoli, A. Ferrari, G. Ferrari, L. Fiorina, F. Giardina, A. Mercato, F. Novazzi, G. Ratano, B. Rossi, I. M. Sciabica, M. Tallarita, and E. Vecchio Nepita (Virology Resident); M. Calvi and M. Tizzoni (Pharmacy Unit); and C. Nicora, A. Triarico, V. Petronella, C. Marena, A. Muzzi, and P. Lago (Hospital Management). CONFLICT OF INTERESTS The authors declare that there are no conflict of interests. AUTHOR CONTRIBUTIONS IC, FN, FG, FS, MS, SP, RB, FM, FB, and the other members of the San Matteo Pavia COVID‐19 Task Force listed reviewed and approved the manuscript. IC and FN discussed results, data analysis, and wrote the paper. FG, FS, and MS collected the samples. SP, RB, and FM discussed results. FB conceived the study.
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              Detection of specific antibodies to severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein for serodiagnosis of SARS coronavirus pneumonia.

              We report the evaluation of recombinant severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) nucleocapsid protein enzyme-linked immunosorbent assay (ELISA)-based antibody tests for serodiagnosis of SARS-CoV pneumonia and compare the sensitivities and specificities of this ELISA for detection of immunoglobulin G (IgG), IgM, IgA, and their combinations with serum samples from 149 healthy blood donors who donated blood 3 years ago as controls and 106 SARS-CoV pneumonia patients in Hong Kong. The specificities of the ELISA for IgG, IgM, and IgA detection were 95.3, 96.6, and 96.6%, respectively, with corresponding sensitivities of 94.3, 59.4, and 60.4%, respectively. The present ELISA appears to be a sensitive test for serodiagnosis of SARS-CoV pneumonia, is much more economical and less labor-intensive than the indirect immunofluorescence assay, and does not require cultivation of SARS-CoV.

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                July 01 2020
                : m2516
                © 2020

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