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. 2022 Dec 16;10:923525. doi: 10.3389/fpubh.2022.923525

Accuracy of serological tests for COVID-19: A systematic review and meta-analysis

Xiaoyan Zheng 1,, Rui hua Duan 2,, Fen Gong 2, Xiaojing Wei 3, Yu Dong 3, Rouhao Chen 3, Ming yue Liang 3, Chunzhi Tang 3,*, Liming Lu 3,*
PMCID: PMC9800917  PMID: 36589993

Abstract

Objective

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

Methods

PubMed, Embase and the Cochrane Library were searched from January 1 2020 to September 2 2022. We included studies that measured the sensitivity, specificity or both qualities of a COVID-19 serological test and a reference standard of a viral culture or reverse transcriptase polymerase chain reaction (RT–PCR). The risk of bias was assessed by using quality assessment of diagnostic accuracy studies 2 (QUADAS-2). The primary outcomes included overall sensitivity and specificity, as stratified by the methods of serological testing [enzyme-linked immunosorbent assays (ELISAs), lateral flow immunoassays (LFIAs) or chemiluminescent immunoassays (CLIAs)] and immunoglobulin classes (IgG, IgM, or both). Secondary outcomes were stratum-specific sensitivity and specificity within the subgroups, as defined by study or participant characteristics, which included the time from the onset of symptoms, testing via commercial kits or an in-house assay, antigen target, clinical setting, serological kit as the index test and the type of specimen for the RT–PCR reference test.

Results

Eight thousand seven hundred and eighty-five references were identified and 169 studies included. Overall, we judged the risk of bias to be high in 47.9 % (81/169) of the studies, and a low risk of applicability concerns was found in 100% (169/169) of the studies. For each method of testing, the pooled sensitivity of the ELISAs ranged from 81 to 82%, with sensitivities ranging from 69 to 70% for the LFIAs and 77% to 79% for the CLIAs. Among the evaluated tests, IgG (80–81%)-based tests exhibited better sensitivities than IgM-based tests (66–68%). IgG/IgM-based CLIA had the highest sensitivity [87% (86–88%)]. All of the tests displayed high specificity (97–98%). Heterogeneity was observed in all of the analyses. The detection of nucleocapsid protein (77–80%) as the antigen target was found to offer higher sensitivity results than surface protein detection (66–68%). Sensitivity was higher in the in-house assays (78–79%) than in the commercial kits (47–48%).

Conclusion

Among the evaluated tests, ELISA and CLIA tests performed better in terms of sensitivity than did the LFIA. IgG-based tests had higher sensitivity than IgM-based tests, and combined IgG/IgM test-based CLIA tests had the best overall diagnostic test accuracy. The type of sample, serological kit and timing of use of the specific tests were associated with the diagnostic accuracy. Due to the limitations of the serological tests, other techniques should be quickly approved to provide guidance for the correct diagnosis of COVID-19.

Keywords: serological tests, COVID-19, systematic review, meta-analysis, RT–PCR

Introduction

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has affected 219 countries and territories, with 614,385,693 confirmed cases; additionally, 6,522,600 deaths have been reported by the World Health Organization last update 30 September 2022. Accurate and rapid diagnostic tests are critical in achieving the global control of COVID-19. There are two main diagnostic tests for COVID-19: molecular tests that detect viral RNA, and serological tests that detect anti-SARS-CoV-2 immunoglobulin (1). Reverse transcription polymerase chain reaction (RT–PCR) is the gold standard diagnostic test recommended by the current guidelines (2). However, RT–PCR exhibits its own limitations, including inappropriate specimen collection techniques, viral load time since the time of exposure (3) and the source of the specimen, which can contribute to false-negative test results (4). The rates of false-positive RT–PCR performance on the day of the onset of symptoms are 100% but decrease to 38% 5 days later (5). Serological testing is a blood test that can detect specific antibodies against COVID-19, including immunoglobulin M (IgM), IgG and IgA antibodies. Serological tests have been developed as supplementary diagnostic methods, as they can take several days or weeks to develop antibodies after viral exposure; therefore, they can provide information about recent or prior infections (1). As such, serological tests can be used as surveillance tools to better understand the overall infection rate in different regions and populations wherein quantitative PCR assays are not available or are delayed (6). Given the importance of serological tests in combating COVID-19, systematic reviews and meta-analyses that aim to summarize the accuracy parameters of serological tests and to investigate whether they are sufficiently specific or sensitive to achieve their role in practice are urgently needed.

Although some studies have compared pooled sensitivities and specificities of serological test methods, as well as identifying study and patient characteristics (710), high-quality evidence supporting the use of antibody tests for COVID-19 in practice is missing, due to a fast-growing field; additionally, ongoing updates of this systematic review will be implemented (11). Therefore, we conducted a systematic review and meta-analysis to assess the diagnostic accuracy of serological tests for COVID-19 infection. We aimed to understand the global serological tests of coronavirus with maps and updates on the overall sensitivity and specificity. To reduce variability in the estimates and to enhance generalizability, both sensitivity and specificity were stratified by clinical setting (outpatient vs. inpatient), antigen target, serological kit as the index test and the number of days that elapsed since the onset of symptoms. Analyses on the sensitivity and specificity of the different testing methods were performed to provide scientific guidance for the design and evaluation of vaccines and therapeutic antibodies in the future (1).

Methods

Search strategy

This meta-analysis was conducted according to the Preferred Reporting Project for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (12) and recommends best practices (13). We searched the PubMed, Embase and the Cochrane Library. The search terms used were (SARS-CoV-2 OR Coronavirus disease 2019 OR COVID-19) AND (IgM OR IgG). The searches ends September 2, 2022, with no restrictions on language. The detailed search strategy is in Supplementary material.

Types of studies

We included studies that met the following criteria. (1) Eligible studies, including randomized trials, cohort studies, or case-control studies, and case series reporting sensitivity, specificity, or both qualities of serological testing for COVID-19. (2) Studies evaluating any test that detects antibodies to SARS-CoV-2, including laboratory-based methods and tests designed for use in field therapy. Test methods include: laboratory-based enzyme-linked immunosorbent assay (ELISA) and chemiluminescence immunoassay (CLIA). Rapid diagnostic tests use lateral flow assays (LFIA), including colloidal gold or fluorescently labeled immunochromatographic assays (CGIA or FIA). (3) Serological diagnostic tests not limited to any antibodies, antigens or test methods.

The exclusion criteria were as follows: (1) case reports, review articles and editorials; (2) studies that focus on ineligible populations, such as vaccinated patients and people not infected with the coronavirus.

Three different researchers independently screened literature, extracted data and validated the results. If there is an objection, resolve it by discussion or negotiation with a third researcher.

Participants

We included studies that recruited people with suspicion of current or previous SARS-CoV-2 infection confirmed by NAT (such as RT PCR or sequencing) or NAT in combination with clinical outcomes.

Outcomes

The primary outcomes included overall sensitivity and specificity, stratified by serological tests (ELISA, LFIA, and CLIA) and immunoglobulin class (IgG, IgM, or both). Secondary outcomes include layer-specific sensitivity and specificity within subgroups, defined by study or participant characteristics.

Data extraction and bias assessment

The following data were independently extracted by 2 professional researchers: general study details (authors, year of publication, country of origin, study design, sample size, reagent company, time from symptom onset to index test and clinical setting and whether testing was performed via commercial kits or an in-house assay), methods, characteristics and diagnostic test results [true positive (TP), true negative (TN), false-positive (FP), false negative (FN), sensitivity, specificity and accuracy] (7).

Two researchers independently assessed the risk of bias for each study using the Cochrane Collaboration recommended Diagnostic Precision Study Quality Assessment Tool (QUADAS-2) (14). Quadas-2 is a quality assessment tool developed specifically for the systematic evaluation of accuracy studies, covering the following four key areas: patient selection, index test, reference standard and flow and timing. Additionally, each area was divided into low risk, high risk and unclear risk. The tool classifies evidence from observational studies into “low risk of bias,” “unclear” and “high risk of bias” level. If at least 50% of the fields are classified as low bias risk, the overall risk of bias for individual studies is classified as low bias risk; Otherwise, a higher risk of bias is defined (15).

Statistical analysis

Sensitivity and specificity of calculated estimates for each individual study (based on 2 × 2 contingency tables). All of the results are reported with 95% confidence intervals (CIs). Data are summarized as paired Forest plots. Since different studies have different cutoff values, a two-variable random effects model was used for meta-analysis. A summary receiver operating characteristic (ROC) curve based on TP and FP rates was established to describe the relationship between detection sensitivity and specificity. The area under the curve (AUC) is close to 1, indicating that the test has good diagnostic performance. All of the analyses were performed using Meta-Disc version 1.4.7. Random effects logistic regression model was used to compare the diagnostic accuracy of different antibodies, different antibody detection methods and different antigens. The heterogeneity of the study was determined by summary ROC curves with 95% prediction regions, estimated using bivariate meta-analysis with a test level random effect only, and forest plots. As our models were bivariate, we did not use the I2 statistic.

In the subgroup analysis, to assess pre-specified variables as potential determinants of diagnostic accuracy, we collected samples at times associated with symptom onset (at week 1, week 2, at week 3, or after week 3); Depending on the antigen target [surface protein (S), nucleocapsid protein (N), surface and nucleocapsid protein], the test is performed using a commercial kit or an internal test; Clinical institutions (inpatient, outpatient, inpatient, outpatient only); Serological kits as indicative tests (using commercial kits or in-house tests); and the type of specimen used for RT PCR reference testing (nasopharyngeal or sputum, saliva or oral, throat and pharyngeal). In these analyses, we pooled data according to the test method (ELISA, LFIA and CLIA) and immunoglobulin class (IgM, IgG or both).

Patient and public involvement

Patients were not involved in the formulation of study questions or outcome measurements, the conduct of the study or the preparation of the manuscript (7).

Results

Description of included studies

Figure 1 shows the selection of the studies. A total of 8,785 articles were identified after the removal of duplicate articles. Of these articles, 2,056 articles were excluded during the screening phase (title and abstract reading), with 6,560 records being fully appraised. Finally, 169 articles met the inclusion criteria.

Figure 1.

Figure 1

Study selection.

Participant characteristics

Table 1 summarizes the studies by test method; the sum of the number of studies exceeded 169 because some studies evaluated more than one method. For example, a study that assessed 2 LFIAs and 3 ELISAs on the same set of patients would contribute 5 study arms. Twenty percent (33/169) of the studies were from the United States, Fifteen percent (26/169) of the studies were from China and the remainder of the studies were from Italy (12/169), Germany (9/169), Belgium (8/169), France (7/169), Japan (6/169), UK (6/169), Australia (5/169), Spain (5/169), Switzerland (5/169), Brazil (4/169), Saudi Arabia (4/169), Singapore (4/169), Austria (3/169), Sweden (3/169), Canada (2/169), Ecuador (2/169), Liechtenstein (2/169), Netherlands (2/169), Thailand (2/169), Bangladesh (1/169), Chile (1/169), Colombia (1/169), Croatia (1/169), Finland (1/169), Greece (1/169), India (1/169), Iran (1/169), Israel (1/169), Kenya (1/169), Korea (1/169), Mexico (1/169), New Zealand (1/169), Nigeria (1/169), Qatar (1/169), Serbia (1/169), South Africa (1/169), Uganda (1/169), and United Arab Emirates (1/169). Three SARS-CoV-2 antigens, including surface protein (S), nucleocapsid protein (N) and envelope protein (E), were used either together or separately in the studies that were included in the review. The spike protein was used as the antigen in 31 study arms, and the nucleocapsid protein was used in 21 study arms. Fifty-two study arms separately used both S and N as antigens. In 19 study arms, S and N antigens (S-N) were used together as the antigen. In 17 study arms, N and E antigens (N-E) were used together as the antigen. The sample was collected from inpatients in 48 articles and in 11 articles regarding outpatients. Fifty-nine study arms were separately comprised of outpatients and inpatients. In 42 study arms, samples were collected from inpatients and outpatients together. Most of the serological assay test kits were commercial (n = 173 study arms), and 22 study arms involved in-house assays. When regarding the type of specimen used for the RT–PCR reference test, 70 study arms involved nasopharyngeal samples, and 47 study arms involved sputum, saliva or oral, throat and pharyngeal samples. Table 1 reports the characteristics of each individual study.

Table 1.

Summary of characteristics of included studies, stratified by method of serological testing.

ELISA CLIA LFIA
Characteristics No. of studies No. of participants COVID-19/healthy No. of studies No. of participants COVID-19/healthy No. of studies No. of participants COVID-19/healthy
Total 94 32,584 8,265/24,319 63 24,326 6,308/18,018 50 15,063 5,266/9,797
Australia 4 2,472 352/2,120 1 209 71/138 2 476 143/333
Austria 2 240 81/159 1 571 230/341
Bangladesh 1 184 79/105
Belgium 5 1,010 550/460 4 691 362/329 3 608 333/275
Brazil 2 633 423/210 1 228 134/94 2 524 371/153
Canada 1 160 49/111 2 340 122/218
China 8 2,060 1,105/955 16 6,052 2,851/3,201 9 1,609 806/803
Colombia 1 142 83/59
Croatia 1 160 60/100 1 160 60/100 1 160 60/100
Denmark 1 736 150/586
Ecuador 1 127 78/49
Finland 1 151 70/81
France 2 395 154/241 4 398 157/241 2 1,084 690/394
Germany 6 13,408 1,266/12,142 3 422 229/193 1 50 25/25
Greece 1 200 50/150
India 1 50 25/25
Iran 1 179 67/112
Israel 1 633 309/324
Italy 6 5,541 509/5,032 5 5,489 400/5,089 4 4,861 366/4,495
Japan 1 317 143/174 3 1,265 397/868 3 549 235/314
Liechtenstein 1 1,338 145/1,193
Kenya 1 665 149/516
Korea 1 149 70/79
Mexico 1 378 149/229
Netherlands 1 228 99/129 2 544 196/348
New Zealand 1 134 21/113
Nigerian 1 195 96/99
Qatar 1 171 101/70
Saudi Arabia 4 881 291/590
Serbia 1 118 50/68
Spain 2 436 200/236 5 710 460/250
Singapore 4 2,021 660/1,361
South Africa 1 512 373/139
Sweden 2 485 239/246 2 399 199/200 1 302 152/150
Switzerland 4 2,353 451/1,902 2 1,450 327/1,123 1 91 41/50
Thailand 2 615 436/179
Uganda 1 150 50/100
United Arab Emirates 1 93 63/30 1 93 63/30
UK 2 233 133/100 2 530 286/244 3 1,695 490/1,205
USA 24 14,419 3,224/11,195 8 5,647 1,041/4,606 9 3,993 2,121/1,872
Time post-onset
First week 12 4,310 1,428/2,882 12 10,452 1,869/8,583 11 2,185 1,348/837
Second week 11 11,594 1,203/10,391 11 3,079 1,139/1,940 7 4,106 829/3,277
Third week 22 12867 3310/9607 16 8807 2604/6203 13 3055 1,693/1,362
Third week later (22–28 day) 9 5,274 1,788/3,486 10 5,805 1,771/2,034 7 2,671 1,015/1,656
Antigen target
Surface protein 28 10,510 3,427/7,083 10 2,927 1,579/1,348 1 105 30/75
Nucleocapsid protein 22 16,359 1,748/14,611 7 3,332 800/2,532 4 873 415/458
Surface and nucleocapsid proteins 18 5,385 1,912/3,473 9 6,101 1,655/4,446 5 1,096 511/585
Clinical setting
Inpatient only 21 5,896 1,822/4,074 18 6,354 2,536/3,818 10 1,822 889/933
Outpatient 7 6,408 692/5,716 2 2,709 170/2,539 4 5,103 456/4,647
Inpatient and outpatient 18 10,636 3,072/7,564 19 11,502 3,005/8,497 11 3,261 1,518/1,743
No reported 46 27,033 5,731/21,352 25 9,090 2,898/6,192 32 11,125 4,415/6,710
Serological kit as index test
Commercial serological kit 81 45,393 9,592/35,851 55 23,704 7,024/16,680 50 20,426 6,905/13,521
In-house assay 16 5,397 2,233/3,164 5 4,134 990/3,144 2 2,275 1,289/986
Unclear 1 736 150/586 2 302 141/161 6 1,059 402/657
Type of specimen for RT–PCR reference test
Nasopharyngeal 36 15,480 3,878/11,602 19 10,564 1,800/8,764 19 7,122 3,694/3,428
Sputum, saliva, or oral, throat, or pharyngeal 21 9,893 2,343/7,550 13 6,257 1,728/4,529 15 8,579 2,389/6,190
Not reported 44 31,019 6,379/24,690 36 14,664 5,010/9,654 29 8,865 2,872/5,993

TP, true positive; FN, false negative; TN, true negative; FP, false positive; ELISA, enzyme linked immunosorbent assay; LFIA, lateral flow immunoassay; CLIA, chemiluminescent immunoassay.

Methodological qualities of the included studies

Figure 2 summarizes the QUADA-2 assessment, and Supplementary Table S1 provides details for each study QUADAS-2 evaluations. For the patient selection domain, a high or unclear risk of bias was observed in 98% (166/169) of the QUADAS-2 assessments, with the risks of bias mostly related to a case-control design and not due to conductive or random sampling. For the index test domain, 99% (167/169) of the assessments demonstrated a high or unclear risk of bias because it was not clear whether the serological test was interpreted blindly to the reference standard or whether the cut-off values for classifying the results were positive or negative. For the reference standard domain, 99% (167/169) of the assessments concluded a low risk of bias because the RT–PCR test is currently the best diagnostic method for use in novel coronavirus patients and is evaluated without knowing the results of the novel coronavirus serum test. The risk of bias from flow and timing was high or unclear in 27.2% (46/169) of the assessments, which was due to an appropriate time interval between the new coronavirus serum test that we investigated and the gold standard RT–PCR test. All of the patients underwent the same gold standard test, and most of the researched cases were included in the analysis.

Figure 2.

Figure 2

Quality assessment of QuaDas-2 assessment.

Overall sensitivity

Table 2 reports on the sensitivity that was stratified by test type and immunoglobulin class. Within each test method (CLIA, ELISA, and LFIA), point estimates were similar between the different types of immunoglobulins, and the confidence intervals overlapped. Within each class of immunoglobulin, the sensitivity was lowest for the LFIA method. The pooled sensitivity of the ELISAs measuring IgM was 71% (95% CI: 70–73%), with IgG being 84% (95% CI: 83–84%) and IgM or IgG being 84% (95% CI: 83–85%). The pooled sensitivity of the LFIAs measuring IgM was 65% (95% CI: 64–67%), with IgG being 73% (95% CI: 71–74%) and IgM/IgG being 69% (95% CI: 68–71%). The pooled sensitivity of the CLIAs measuring IgM was 70% (95% CI: 69–72%), with IgG being 80% (95% CI: 79–81%) and IgM/IgG being 87% (95% CI: 86–88%). For all of the test methods and immunoglobulin classes, visual inspections of the summary ROC curves (Supplementary Figure S1) and of the forest plots (Supplementary Figure S2) exhibited significant heterogeneity.

Table 2.

Individual and pooled sensitivity by serological test method and immunoglobulin class detected.

IgM IgG IgM or IgG
Method and studies TP FN Sensitivity (%) (95% CI) TP FN Sensitivity (%) (95% CI) TP FN Sensitivity (%) (95% CI)
ELISA (n = 94 arms)
A Cramer (2021) 378 62 85.9 (82.3–89.0)
Abdullah Algaissi (2020) 26 78 25.0 (17.0–34.4) 60 44 57.7 (47.6–67.3)
Alexander Krüttgen (2020) 65 10 86.7 (76.8–93.4)
Angel Guevara (2021) 73 5 93.6 (85.7–97.9)
Anita S. Iyer (2020) 210 49 81.1 (75.8–85.7) 251 8 96.9 (94.0–98.7)
Antoine-Reid. T (2020) 18 3 85.7 (63.7–97.0)
Archana Thomas (2021) 36 14 72.0 (57.5–83.8)
Ariel D. Stock (2020) 4 4 50.0 (15.7–84.3)
Ayesha Appa (2020) 39 46 45.9 (35.0–57.0) 76 94 44.7 (37.1–52.5)
B. Meyer (2020) 170 11 93.9 (89.4–96.9)
Bijon Kumar Sil (2021) 75 4 94.9 (87.5–98.6)
Bin Lou (2020) 74 6 92.5 (84.4–97.2) 71 9 88.8 (79.7–94.7)
Carleen Klumpp-Thomas (2020) 194 95 67.1 (61.4–72.5)
Caturegli. G (2020) 301 7 97.7 (95.4–99.1)
Chang Zhou (2020) 150 0 100 (97.6–100.0) 149 1 99.3 (96.3–100)
Christian Wechselberger (2020) 50 1 98.0 (89.6–100)
Clarence W. Chan (2020) 74 4 94.9 (87.4–98.6) 146 23 86.4 (80.3–91.2)
D. S. Y. Ong (2020) 193 96 66.8 (61.0–72.2)
Daniel Brigger (2020) 281 55 83.6 (79.2–87.4)
David M (2020) 79 5 94.0 (86.7–98.0) 81 2 97.6 (91.6–99.7)
E. Catry (2020) 16 2 88.9 (65.3–98.6)
Ekasit Kowitdamrong (2020) 84 15 84.8 (76.2–91.3)
Eshan U. Patel (2020) 127 19 87.0 (80.4–92.0)
Fei Xiang (2020) 51 15 77.3 (65.3–86.7) 55 11 83.3 (72.1–91.4)
Gang Xu (2020) 26 0 100 (86.8–100)
Giuseppe Vetrugno (2021) 129 35 78.7 (71.6–84.7)
Gláucia Cota (2020) 242 47 83.7 (79.0–87.8)
Hadi M. Yassine (2020) 382 123 75.6 (71.7–79.3)
Isabel Montesinos (2020) 79 49 61.7 (52.7–70.2)
Isabelle Piec (2021) 214 37 85.3 (80.3–89.4)
Iyer. A S (2020) 278 65 81.0 (76.5–85.1) 326 17 95.0 (92.2–97.1)
Jeffrey D. Whitman (2020) 192 64 75.0 (69.2–80.2)
Jialin Xiang (2020) 20 6 76.9 (56.4–91.0) 20 6 76.9 (56.4–91.0)
Jira Chansaenroj (2021) 176 47 78.9 (73.0–84.1)
Joanna Jung (2020) 104 0 100 (96.5–100)
Julien Favresse (2020) 750 340 68.8 (66.0–71.5)
Julien Marlet (2020) 183 49 78.9 (73.1–83.9)
Justin Manalac (2020) 97 0 100 (96.3–100)
Katherine Bond (2020) 85 6 93.4 (86.2–97.5)
Kristin E. Mullins (2021) 277 5 98.2 (95.9–99.4)
Lene H. Harritsh (2021) 187 113 62.3 (56.6–67.8) 281 9 96.9 (94.2–98.6) 289 11 96.3 (93.5–98.2)
Luciano F. Huergo (2021) 516 50 91.2 (88.5–93.4)
Marc Kovac (2020) 147 142 50.9 (44.9–56.8)
Margherita Bruni (2020) 54 2 96.4 (87.7–99.6)
Maria Martínez Serrano (2020) 106 24 81.5 (73.8–87.8)
Marie Tré-Hardy (2020) 12 27 30.8 (17.0–47.6) 42 2 95.5 (84.5–99.4)
Marzia Nuccetelli (2020) 88 4 95.7 (89.2–98.8)
Marzia Nuccetelli (2021) 84 3 96.6 (92.6–98.7)
Massimo Pieri (2020) 30 10 75.0 (58.8–87.3) 75 5 93.8 (86.0–97.9)
Maximilian Kittel (2020) 137 46 74.9 (67.9–81.0)
Melkon G. DomBourian (2020) 92 10 90.2 (82.7–95.2)
N. Davidson (2020) 16 131 10.9 (6.4–17.1) 86 56 60.6 (52.0–68.7)
Qiang Wang (2020) 14 0 100 (76.8–100)
Reuben McGregor (2020) 4 17 19.0 (5.4–41.9) 21 0 100 (83.9–100) 21 0 100 (83.9–100)
Sarah E. Turbett (2020) 90 38 70.3 (61.6–78.1)
Sarah M. Hicks (2020) 43 0 100 (91.8–100)
Stefani N. Thomas (2021) 68 11 86.1 (76.5–92.8)
Suliman A. Alharbi (2020) 35 5 87.5 (73.2–95.8) 37 3 92.5 (79.6–98.4)
Tania ReginaTozetto-Mendoza (2021) 121 13 90.3 (84.0–94.7)
Teodora Djukic (2021) 47 3 94.0 (83.5–98.7) 47 3 94.0 (83.5–98.7)
Teresa Stock da Cunha (2020) 40 8 83.3 (69.8–92.5) 48 0 100 (92.6–100)
Thamir A. Alandijany (2020) 109 0 100 (96.7–100)
Thomas Nicol (2020) 141 0 100 (97.4–100)
Thomas W. McDade (2020) 27 3 90.0 (73.5–97.9)
Traugott M (2020) 8 22 26.7 (12.3–45.9) 1 29 3.3 (1.0–17.2) 11 19 36.7 (19.9–56.1)
Victoria Indenbaum (2020) 133 148 47.3 (41.4–53.3) 271 36 88.3 (84.1–91.7)
Wanbing Liu (2020) 146 68 68.2 (61.5–74.4) 150 64 70.1 (63.5–76.1) 172 42 80.4 (74.4–85.5)
Zahra Rikhtegaran Tehrani (2020) 234 57 80.4 (75.4–84.8) 179 21 89.5 (84.4–93.4)
Brad Poore (2021) 173 19 90.0 (85.0–94.0)
Valentina Pecoraro (2021) 20 4 83.0 (63.0–95.0) 22 2 92.0 (73.0–99.0)
James Nyagwange (2021) 138 11 93.0 (87.0–96.0) 142 7 95.0 (91.0–98.0)
Pan-pan Liu (2021) 160 8 95.0 (91.0–98.0) 163 5 97.0 (93.0–99.0) 168 0 100.0 (98.0–100.0)
Maryam Ranjbar (2021) 62 5 93.0 (83.0–98.0) 61 6 91.0 (82.0–97.0)
Marina Bubonja-Šonje (2021) 58 2 97.0 (88.0–100.0) 44 16 73.0 (60.0–84.0)
Tom Lutalo (2021) 33 17 66.0 (51.0–79.0) 49 1 98.0 (89.0–100.0) 46 4 92.0 (81.0–98.0)
Oskar Ekelund (2021) 150 2 99.0 (95.0–100.0)
P. J. Ducrest (2021) 21 2 91.0 (72.0–99.0)
Norihito Kaku (2021) 112 31 78.0 (71.0–85.0)
David Triest (2021) 108 0 100.0 (97.0–100.0)
Maemu P. Gededzha (2021) 239 134 64.0 (59.0–69.0)
Robert Needle (2021) 48 0 100.0 (93.0–100.0)
Arwa A. Faizo (2021) 90 0 100.0 (96.0–100.0)
Rosa Camacho-Sandoval (2021) 148 1 99.0 (96.0–100.0)
Theano Lagousi (2021) 35 15 70.0 (55.0–82.0) 46 4 92.0 (81.0–98.0)
Adnan Alatoom (2021) 27 5 84.0 (67.0–95.0)
Fehintola Ige (2021) 68 28 71.0 (61.0–80.0)
Ingrid Sander (2022) 91 5 95.0 (88.0–98.0)
Shiji Wu (2022) 329 55 86.0 (82.0–89.0) 368 16 96.0 (93.0–98.0)
Vijayalakshmi Nandakumar (2021) 116 8 94.0 (88.0–97.0)
Elena Riester (2021) 116 8 94.0 (88.0–97.0)
Ismar A. Rivera-Olivero (2022) 106 21 83.0 (76.0–89.0)
Nina Lagerqvist (2021) 71 16 82.0 (72.0–89.0)
Ji Luo (2021) 61 7 90.0 (80.0–96.0)
Suellen Nicholson (2021) 72 72 50.0 (42.0–58.0)
Pooled 2,451 980 71.0 (70.0–73.0) 9,418 1,820 84.0 (83.0–84.0) 3,589 686 84.0 (83.0–85.0)
LFIA (n = 55 arms)
A Cramer (2021) 62 16 79.5 (68.8–87.8)
Chao Huang (2020) 5 0 100 (47.8–100)
Choe JY (2020) 65 5 92.9 (84.1–97.6)
Clarence W (2021) 90 9 90.9 (83.4–95.8)
D. S. Y. Ong (2020) 43 56 43.3 (33.5–53.8)
Diego O. Andrey (2020) 40 6 87.0 (73.7–95.1)
E Tuaillon (2020) 12 3 80.0 (51.9–95.7) 13 2 86.7 (59.5–98.3)
E. Catry (2020) 43 1 97.7 (88.0–99.9) 39 13 75.0 (61.1–86.0) 25 1 96.2 (80.4–99.9)
Feng M (2020) 27 1 96.4 (81.7–99.9) 27 1 96.4 (81.7–99.9)
Francis Stieber (2020) 30 0 100 (88.4–100)
Francisco Javier Candel González (2020) 35 0 100 (90.0–100)
Giovanni Sotgiu (2020) 6 1 85.7 (42.1–99.6) 4 3 57.1 (18.4–90.1)
Giuseppe Vetrugno (2021) 104 60 63.4 (55.5–70.8)
Gladys VirginiaGuedez-López (2020) 28 22 56.0 (41.3–70.0) 26 24 52.0 (37.4–66.3) 268 167 61.6 (56.9–66.2)
Gláucia Cota (2020) 1,260 484 72.2 (70.1–74.3)
Hua Li (2020) 68 7 90.7 (81.7–96.2) 51 23 68.9 (57.1–79.2) 69 6 92.0 (83.4–97.0)
Isabel Montesinos (2020) 238 146 62.0 (56.9–66.9) 271 113 70.6 (65.7–75.1)
J. Van Elslande (2020) 60 93 39.2 (31.4–47.4) 95 58 62.1 (53.9–69.8) 100 53 65.4 (57.3–72.9)
Jeffrey D. Whitman (2020) 691 427 61.8 (58.9–64.7) 658 461 58.8 (55.9–61.7) 62 411 13.1 (10.2–16.5)
Kathrine McAulay (2020) 312 23 93.1 (89.9–95.6)
Klaus Puschel (2021) 176 128 57.9 (52.1–63.5)
Laurent Dortet (2020) 525 243 68.4 (64.9–71.6)
Linda Hueston (2020) 78 48 61.9 (52.8–70.4) 113 13 89.7 (83.0–94.4) 78 48 61.9 (52.8–70.4)
Lixia Zhang (2020) 120 7 94.5 (89.0–97.8) 121 6 95.3 (90.0–98.2)
Maria Martínez Serrano (2020) 41 85 32.5 (24.5–41.5) 89 37 70.6 (61.9–78.4)
Marta Cancella de Abreu (2020) 103 34 75.2 (67.1–82.2)
Maya Moshe (2021) 164 18 90.1 (84.8–94.0) 161 30 84.3 (78.3–89.1)
Morihito Takita (2020) 5 0 100 (47.8–100)
Niko Kohmer (2020) 13 4 76.5 (50.1–93.2)
Peter Findeisen (2020) 42 0 100 (91.6–100)
Qiang Wang (2020) 14 0 100 (76.8–100)
Roselle S. Robosa (2020) 27 27 50.0 (36.1–63.9) 30 25 54.5 (40.6–68.0) 35 25 58.3 (44.9–70.9)
Scott J C Pallett (2020) 375 37 91.0 (87.8–93.6)
Shun Kaneko (2020) 69 18 79.3 (69.3–87.3) 75 6 92.6 (84.6–97.2)
SilviaMontolio Breva (2021) 46 17 73.0 (60.3–83.4)
Thomas Nicol (2020) 141 0 100 (97.4–100) 141 0 100 (97.4–100)
Tian Wen (2020) 38 17 69.1 (55.2–80.9)
Vani Maya (2021) 23 2 91.0 (74.0–99.0)
Won Lee (2020) 44 6 88.0 (75.7–95.5) 42 8 84.0 (70.9–92.8)
Yaqing Li (2020) 72 17 80.9 (71.2–88.5)
Yunbao Pan (2020) 48 38 55.8 (44.7–66.5) 47 39 54.7 (43.5–100) 59 27 68.6 (57.7–78.2)
Zahra Rikhtegaran Tehrani (2020) 82 18 82.0 (73.1–89.0) 92 8 92.0 (84.8–96.5)
Ziad Daoud (2020) 156 64 70.9 (64.4–76.8) 159 61 72.3 (65.9–78.1)
Jialin Xiang (2020/10) 13 37 26.0 (14.6–40.3)
Valentina Pecoraro (2021) 16 8 67.0 (45.0–84.0) 22 2 92.0 (73.0–99.0)
Marina Bubonja-Šonje (2021) 60 0 100.0 (94.0–100.0) 46 14 77.0 (64.0–87.0)
Bianca A. Trombetta (2021) 51 5 91.0 (80.0–97.0) 52 4 93.0 (83.0–98.0) 51 5 91.0 (80.0–97.0)
Oskar Ekelund (2021) 110 42 72.0 (65.0–79.0)
Norihito Kaku (2021) 33 110 23.0 (16.0–31.0) 69 74 48.0 (40.0–57.0)
Sérgio M. de Almeida (2021) 68 14 83.0 (73.0–90.0) 59 23 72.0 (61.0–81.0) 69 13 84.0 (74.0–91.0)
Amedeo De Nicolò (2021) 80 63 56.0 (47.0–64.0)
Dennis Souverein (2021) 17 80 18.0 (11.0–27.0) 77 20 79.0 (70.0–87.0) 78 19 80.0 (71.0–88.0)
Sophie I. Owen (2021) 67 33 67.0 (57.0–76.0) 51 49 51.0 (41.0–61.0) 70 30 70.0 (60.0–79.0)
Shiji Wu (2022) 268 116 70.0 (65.0–74.0) 353 31 92.0 (89.0–94.0)
Ismar A. Rivera-Olivero (2022) 101 26 80.0 (71.0–86.0) 101 26 80.0 (71.0–86.0)
Pooled 2,692 1,441 65.0 (64.0–67.0) 2,872 1,070 73.0 (71.0–74.0) 4,989 2,190 69.0 (68.0–71.0)
CLIA (n = 64 arms)
Bin Lou (2020) 69 11 86.3 (76.7–92.9) 69 11 86.3 (76.7–92.9)
Dachuan Lin (2020) 48 31 60.8 (49.1–71.6) 65 14 82.3 (72.1–90.0)
Wanbing Liu (2020) 149 57 72.3 (65.7–78.3) 40 4 90.9 (78.3–97.6)
Maria Infantino (2020) 45 16 73.8 (60.9–84.2) 47 14 77 (64.5–86.8)
Shao Lijia (2020) 9 6 60 (32.3–83.7) 22 3 88 (68.8–97.5)
Fang Hu (2020) 51 17 75 (63.0–84.7) 57 11 83.8 (72.9–91.6) 104 12 89.7 (82.6–94.5)
Charpentier, C (2020) 4 2 66.7 (22.3–95.7)
Jääskeläinen, A J (2020) 56 14 80 (68.7–88.6)
Ping li (2020) 88 28 75.9 (67.0–83.3) 104 12 89.7 (82.6–94.5)
Chew, K L (2020) 15 162 8.5 (4.8–13.6)
Fabrizio Bonelli (2020) 275 147 65.2 (60.4–69.7)
Narjis Boukli (2020) 292 140 67.6 (63.0–72.0)
Andrew Bryan (2020) 66 59 52.8 (43.7–61.8)
MarinaJohnson (2020) 189 7 96.4 (92.8–98.6)
Niko Kohmer (2020) 35 10 77.8 (62.9–88.8)
Z. Huang (2020) 325 21 93.9 (90.9–96.2)
Ayesha Appa (2020) 12 0 100 (73.5–100)
Chungen Qian (2020) 441 72 86 (82.7–88.9) 496 17 96.7 (94.7–98.1) 77 45 63.1 (53.9–71.7)
Marie Tré-Hardy (2020) 40 81 33.1 (24.8–42.2)
Isabel Montesinos (2020) 74 52 58.7 (49.6–67.4) 67 59 53.2 (44.1–62.1)
Julien Marlet (2020) 49 9 84.5 (72.6–92.7)
Elitza S. Theel (2020) 5 71 6.6 (2.2–14.7)
Massimo Pieri (2020) 30 10 75 (58.8–87.3) 36 4 90 (76.3–97.2) 363 46 88.8 (85.3–91.6)
Thomas Nicol (2020) 141 0 100 (97.4–100)
Morihito Takita (2020) 5 0 100 (47.8–100)
Raymond T (2020) 158 113 58.3 (52.2–64.2) 188 83 69.4 (63.5–74.8) 130 20 86.7 (80.2–91.7)
Justin Manalac (2020) 208 17 92.4 (88.2–95.5) 264 34 88.6 (84.4–92.0)
C. S. Lau (2020) 270 9 96.8 (94.0–98.5)
Yafang Wan (2020) 109 41 72.7 (64.8–79.6) 130 20 86.7 (80.2–91.7) 46 4 92 (80.8–97.8)
E. Catry (2020) 16 2 88.9 (65.3–98.6) 17 1 94.4 (72.7–99.9)
Li-xiang Wu (2020) 126 26 82.9 (76.0–88.5) 138 14 90.8 (85.0–94.9) 146 6 96.1 (91.6–98.5)
Jenna Rychert (2020) 36 3 92.3 (79.1–98.4)
Anja Dörschug (2020) 38 54 41.3 (31.1–52.1)
Nan wu (2020) 9 23 28.1 (13.7–46.7) 25 7 78.1 (60.0–90.7)
Shey-Ying Chen (2020) 325 21 93.9 (90.9–96.2)
Xueping Qiu (2020) 356 53 87 (83.4–90.1) 356 53 87 (83.4–90.1) 364 46 88.8 (85.3–91.7)
Hélène Haguet (2021) 28 110 20.3 (13.9–28.0) 131 7 94.9 (89.8–97.9)
Huihui Wang (2021) 39 1 97.5 (86.8–99.9)
Rasmus Strand MSc (2021) 7 40 14.9 (6.2–28.3) 41 6 87.2 (74.3–95.2)
Tania ReginaTozetto-Mendoza (2021) 121 13 90.3 (84–94.7)
C. S. Lau (2021) 129 4 97 (92.5–99.2)
Luigi Vimercati (2021) 5 13 27.8 (9.7–53.5) 10 8 55.6 (30.8–78.5)
Sousuke Kubo1 (2021) 202 0 100 (98.2–100) 202 0 100 (98.2–100)
Anna Schaffner (2020) 234 117 66.7 (61.5–71.6)
N. DAVIDSON (2020) 45 26 63.4 (51.1–74.5)
A Cramer (2021) 68 7 90.7 (81.7–96.2)
Victoria Higgins (2021) 52 21 71.2 (59.4–81.2) 85 61 58.2 (49.8–66.3) 45 28 61.6 (49.5–72.8)
Myriam C. Weber (2020) 265 25 91.4 (87.5–94.3) 139 6 95.9 (91.2–98.5)
Maximilian Kittel (2020) 112 254 30.6 (25.9–35.6) 324 225 59 (54.8–63.2) 141 97 59.2 (52.7–65.5)
Christian Irsara (2021) 359 62 85.3 (81.5–88.5) 390 35 91.8 (88.7–94.2)
Yaqing Li (2020) 347 10 97.2 (94.9–98.6)
Yuki Nakano (2021) 173 13 93 (88.3–96.2) 164 22 88.2 (82.6–92.4)
Brad Poore (2021) 189 3 59.0 (54.0–65.0)
Valentina Pecoraro (2021) 20 4 83.0 (63.0–95.0) 22 2 92.0 (73.0–99.0)
Gabriel N Maine (2022) 239 11 96.0 (92.0–98.0)
Kotaro Aoki (2021) 135 71 66.0 (59.0–72.0)
Marina Bubonja-Šonje (2021) 58 2 97.0 (88.0–100.0)
Oskar Ekelund (2021) 123 29 81.0 (74.0–87.0)
Lau CS (2021) 68 65 51.0 (42.0–60.0)
Maria del Mar Castro (2021) 69 14 83.0 (73.0–90.0)
Robert Needle (2021) 47 2 96.0 (86.0–100.0)
Adnan Alatoom (2021) 27 5 84.0 (67.0–95.0)
Shiji Wu (2022) 355 29 92.0 (89.0–95.0) 354 30 92.0 (89.0–95.0)
Vijayalakshmi Nandakumar (2021) 117 7 94.0 (89.0–98.0)
Pooled 2,582 1,399 70.0 (69.0–72.0) 6,609 1,683 80.0 (79.0–81.0) 4,009 622 87.0 (86.0–88.0)

Ig, immunoglobulin; TP, true positive; FN, false negative; TN, true negative; FP, false positive; ELISA, enzyme linked immunosorbent assay; LFIA, lateral flow immunoassay; CLIA, chemiluminescent immunoassay.

Overall specificity

Table 3 describes the within study and pooled specificities, as stratified by test type and immunoglobulin class. The pooled specificity of the ELISAs measuring IgM was 98% (95% CI: 98–99%), with IgG being 96% (95% CI: 95–96%), and IgM or IgG being 99% (95% CI: 99–99%). The pooled specificity of the LFIAs measuring IgM was 96% (95% CI: 96–97%), with IgG being 97.0% (95% CI: 96–97%) and IgM or IgG being 97% (95% CI: 97–98%). The pooled specificity of the CLIAs measuring IgM was 94% (95% CI: 93–95%), with IgG being 98% (95% CI: 98–99%) and IgM or IgG being 97% (95% CI: 97–97%). Within each class of immunoglobulin, the specificity was the lowest for the IgM-based CLIA tests. All of the tests displayed high specificity (ranging from 93.0 to 99.0%). For all of the test methods and immunoglobulin classes, visual inspections of the summary ROC curves (Supplementary Figure S1) and of the forest plots (Supplementary Figure S3) showed meta-analytical estimates of specificity (with a value of 95%) by using the serological test method and antibody class.

Table 3.

Individual and pooled specificity by serological test method and immunoglobulin class detected.

IgM IgG IgM or IgG
Method and studies TN FP Specificity (95% CI) TN FP Specificity (95% CI) TN FP Specificity (95% CI)
ELISA (n = 94 arms)
A Cramer (2021) 241 9 96.4 (93.3–98.3)
Abdullah Algaissi (2020) 240 10 96.0 (92.8–98.1) 236 14 94.4 (90.8–96.9)
Alexander Krüttgen (2020) 24 1 96.0 (79.6–99.9)
Angel Guevara (2021) 49 0 100 (92.7–100)
Anita S. Iyer (2020) 1,548 0 100 (99.8–100) 1,548 0 100 (99.8–100)
Antoine-Reid. T (2020) 187 53 77.9 (72.1–83.0)
Archana Thomas (2021) 300 0 100 (98.8–100)
Ariel D. Stock (2020) 79 11 87.8 (79.2–93.7)
Ayesha Appa (2020) 246 15 94.3 (90.7–96.7) 492 30 94.3 (91.9–96.1)
B. Meyer (2020) 316 10 96.9 (94.4–98.5)
Bijon Kumar Sil (2021) 102 3 97.1 (91.9–99.4)
Bin Lou (2020) 300 0 100 (98.8–100) 300 0 100 (98.8–100)
Carleen Klumpp-Thomas (2020) 111 5 95.7 (90.2–98.6)
Caturegli. G (2020) 561 7 98.8 (97.5–99.5)
Chang Zhou (2020) 144 6 96.0 (91.5–98.5) 150 150 50.0 (44.2–55.8)
Christian Wechselberger (2020) 46 13 78.0 (65.3–87.7)
Clarence W Chan (2020) 53 0 100 (93.3–100) 57 0 100 (93.7–100)
D. S. Y. Ong (2020) 114 2 98.3 (93.9–99.8)
Daniel Brigger (2020) 1,650 105 94.0 (92.8–95.1)
David M (2020) 172 16 91.5 (86.5–95.1) 188 0 100 (98.1–100)
E. Catry (2020) 100 0 100 (96.4–100)
Ekasit Kowitdamrong (2020) 166 5 97.1 (93.3–99.0)
Eshan U. Patel (2020) 548 14 97.5 (95.9–98.6)
Fei Xiang (2020) 60 0 100 (94.0–100) 57 3 95.0 (86.1–99.0)
Gang Xu (2020) 120 2 98.4 (94.2–99.8)
Giuseppe Vetrugno (2021) 4,290 28 99.4 (99.1–99.6)
Gláucia Cota (2020) 62 54 53.4 (44.0–62.8)
Hadi M. Yassine (2020) 318 32 90.9 (87.3–93.7)
Isabel Montesinos (2020) 71 1 98.6 (92.5–100)
Isabelle Piec (2021) 588 20 96.7 (95.0–98.0)
Iyer. A S (2020) 1,546 2 99.9 (99.5–100) 1,546 2 99.9 (99.5–100)
Jeffrey D. Whitman (2020) 107 1 99.1 (94.9–100)
Jialin Xiang (2020) 37 4 90.2 (76.9–97.3) 39 2 95.1 (83.5–99.4)
Jira Chansaenroj (2021) 130 0 100 (97.2–100)
Joanna Jung (2020) 36 2 94.7 (82.3–99.4)
Julien Favresse (2020) 470 2 99.6 (98.5–99.9)
Julien Marlet (2020) 662 50 93.0 (90.8–94.7)
Justin Manalac (2020) 35 72 32.7 (24.0–42.5)
Katherine Bond (2020) 953 356 72.8 (70.3–75.2)
Kristin E. Mullins (2021) 440 1 99.8 (98.7–100)
Lene H. Harritsh (2021) 979 6 99.4 (98.7–99.8) 1,182 14 98.8 (98.0–99.4) 1,273 6 99.5 (99.0–99.8)
Luciano F. Huergo (2021) 1,019 9 99.1 (98.3–99.6)
Marc Kovac (2020) 82 34 70.7 (61.5–78.8)
Margherita Bruni (2020) 414 22 95.0 (92.5–96.8)
Maria Martínez Serrano (2020) 84 0 100 (95.7–100)
Marie Tré-Hardy (2020) 79 0 100 (95.4–100) 79 2 97.5 (91.4–99.7)
Marzia Nuccetelli (2020) 82 6 93.2 (85.7–97.5)
Marzia Nuccetelli (2021) 118 0 100 (96.9–100)
Massimo Pieri (2020) 40 0 100 (91.2–100) 80 0 100 (95.5–100)
Maximilian Kittel (2020) 91 6 93.8 (87.0–97.7)
Melkon G. DomBourian (2020) 106 0 100 (96.6–100)
N. Davidson (2020) 55 7 259 17 93.8 (90.3–96.4)
Qiang Wang (2020) 50 22 69.4 (57.5–79.8)
Reuben McGregor (2020) 195 0 100 (98.1–100) 195 0 100 (98.1–100) 113 0 100 (96.8–100)
Sarah E. Turbett (2020) 1,259 9 99.3 (98.7–99.7)
Sarah M Hicks (2020) 182 2 98.9 (96.1–99.9)
Stefani N. Thomas (2021) 237 0 100 (98.5–100)
Suliman A Alharbi (2020) 63 2 96.9 (89.3–99.6) 1 4 20.0 (0.5–71.6)
Tania ReginaTozetto-Mendoza (2021) 92 2 97.9 (92.5–99.7)
Teodora Djukic (2021) 66 2 97.1 (89.8–99.6) 67 1 98.5 (92.1–100)
Teresa Stock da Cunha (2020) 150 2 98.7 (95.3–99.8) 149 3 98.0 (94.3–99.6)
Thamir A. Alandijany (2020) 304 5 98.4 (96.3–99.5)
Thomas Nicol (2020) 147 5 96.7 (92.5–98.9)
Thomas W. McDade (2020) 13 2 86.7 (59.5–98.3)
Traugott M (2020) 97 3 97.0 (91.5–99.4) 98 2 98.0 (93.0–99.8) 97 3 97.0 (91.5–99.4)
Victoria Indenbaum (2020) 180 0 100 (98.0–100) 318 6 98.1 (96.0–99.3)
Wanbing Liu (2020) 100 0 100 (96.4–100) 100 0 100 (96.4–100) 100 0 100 (96.4–100)
Zahra Rikhtegaran Tehrani (2020) 870 15 98.3 (97.2–99.0) 591 9 98.5 (97.2–99.3)
Brad Poore (2021) 129 0 100.0 (97.0–100.0)
Valentina Pecoraro (2021) 2 13 13.0 (2.0–40.0) 2 13 13.0 (2.0–40.0)
James Nyagwange (2021) 515 1 100.0 (99.0–100.0) 507 9 98.0 (97.0–99.0)
Pan-pan Liu (2021) 90 0 100 (96.0–100) 90 0 100.0 (96.0–100.0) 90 0 100.0 (96.0–100.0)
Maryam Ranjbar (2021) 109 3 97.0 (92.0–99.0) 110 2 98.0 (94.0–100.0)
Marina Bubonja-Šonje (2021) 100 0 100 (96.0–100) 99 1 99.0 (95.0–100.0)
Tom Lutalo (2021) 90 10 90.0 (82.0–95.0) 98 2 98.0 (93.0–100.0) 89 11 89.0 (81.0–94.0)
Oskar Ekelund (2021) 148 2 99.0 (95.0–100.0)
P. J. Ducrest (2021) 95 3 97.0 (91.0–99.0)
Norihito Kaku (2021) 174 0 100.0 (98.0–100.0)
David Triest (2021) 84 5 94.0 (87.0–98.0)
Maemu P. Gededzha (2021) 132 7 95.0 (90.0–98.0)
Robert Needle (2021) 109 2 98.0 (94.0–100.0)
Arwa A. Faizo (2021) 91 1 99.0 (94.0–100.0)
Rosa Camacho-Sandoval (2021) 224 5 98.0 (95.0–99.0)
Theano Lagousi (2021) 137 13 91.0 (86.0–95.0) 146 4 97.0 (93.0–99.0)
Adnan Alatoom (2021) 30 0 100.0 (88.0–100.0)
Fehintola Ige (2021) 99 0 100.0 (96.0–100.0)
Ingrid Sander (2022) 176 7 96.0 (92.0–98.0)
Shiji Wu (2022) 139 3 98.0 (94.0–100.0) 138 4 97.0 (93.0–99.0)
Vijayalakshmi Nandakumar (2021) 184 8 96.0 (92.0–98.0)
Elena Riester (2021) 9,561 14 100.0 (100.0–100.0)
Ismar A. Rivera-Olivero (2022) 40 0 100.0 (91.0–100.0)
Nina Lagerqvist (2021) 95 1 99.0 (94.0 to100.0)
Ji Luo (2022) 1,489 1 100.0 (100.0–100.0)
Suellen Nicholson (2021) 179 30 86.0 (80.0–90.0)
Pooled 7,712 138 98.0 (98.0–99.0) 26,510 1,219 96.0 (95.0–96.0) 15,059 159 99.0 (99.0–99.0)
LFIA (n = 55 arms)
A Cramer (2021) 20 0 100 (93.2–100)
Chao Huang (2020) 13 1 92.9 (66.1–99.8)
Choe JY (2020) 67 12 84.8 (75.0 to91.9)
Clarence W (2021) 165 3 98.2 (94.9–99.6)
D. S. Y. Ong (2020) 126 3 97.7 (93.4–99.5)
Diego O. Andrey (2020) 44 1 97.8 (88.2–99.9)
E Tuaillon (2020) 19 1 95.0 (75.1–99.9) 20 0 100 (83.2–100)
E. Catry (2020) 288 12 96.0 (93.1–97.9) 396 4 99.0 (97.5–99.7) 200 0 100 (98.2–100)
Feng M (2020) 72 5 93.5 (85.5–97.9) 77 0 100 (95.3–100)
Francis Stieber (2020) 75 0 100 (95.2–100)
Francisco Javier Candel González (2020) 5 0 100 (47.8–100)
Giovanni Sotgiu (2020) 1 21 45.0 (1.0–22.8) 16 6 72.7 (49.8–89.3)
Giuseppe Vetrugno (2021) 4,173 145 96.6 (96.1–97.2)
Gladys VirginiaGuedez-López (2020) 76 19 80.0 (70.5–87.5) 80 15 84.2 (75.3–90.9) 34 26 56.7 (43.2–69.4)
Gláucia Cota (2020) 668 28 96.0 (94.2–97.3)
Hua Li (2020) 136 3 97.8 (93.8–99.6) 138 1 99.3 (96.1–100) 135 4 97.1 (92.8–99.2)
Isabel Montesinos (2020) 213 3 98.6 (96.0–99.7) 213 3 98.6 (96.0–99.7)
J. Van Elslande (2020) 94 9 91.3 (84.1–95.9) 101 2 98.1 (93.2–99.8) 93 10 90.3 (82.9–95.2)
Jeffrey D. Whitman (2020) 900 56 94.1 (92.5–95.5) 933 23 97.6 (96.4–98.5) 1,000 0 100 (99.6–100)
Kathrine McAulay (2020) 416 4 99.0 (97.6–99.7)
Klaus Puschel (2021) 215 3 98.6 (96–99.7)
Laurent Dortet (2020) 150 0 100 (97.6–100)
Linda Hueston (2020) 2,621 8 99.7 (99.4–99.9) 2,607 22 99.2 (98.7–99.5) 2,626 2 99.9 (99.7–100)
Lixia Zhang (2020) 20 0 100 (83.2–100) 20 0 100 (83.2–100)
Maria Martínez Serrano (2020) 79 5 94.0 (86.7–98.0) 83 1 98.8 (93.5–100)
Marta Cancella de Abreu (2020) 16 4 80.0 (6.3–94.3)
Maya Moshe (2021) 500 0 100 (99.3–100) 250 0 100 (98.5–100)
Morihito Takita (2020) 38 2 95.0 (83.1–99.4)
Niko Kohmer (2020) 19 0 100 (82.4–100)
Peter Findeisen (2020) 89 3 96.7 (90.8–99.3)
Qiang Wang (2020) 50 22 69.4 (57.5–79.8)
ROSELLE S. ROBOSA (2020) 71 0 100 (94.9–100) 70 1 98.6 (92.4–100) 70 1 98.6 (92.4–100)
Scott J C Pallett (2020) 286 16 94.7 (91.5–96.9)
Shun Kaneko (2020) 100 0 100 (96.4–100) 100 0 100 (96.4–100)
Silvia Montolio Breva (2021) 59 2 96.7 (88.7–99.6)
Thomas Nicol (2020) 145 7 95.4 (90.7–98.1) 147 5 96.7 (92.5–98.9)
Tian Wen (2020) 30 0 100 (88.4–100)
Vani Maya (2021) 25 0 100 (86.3–100)
Won Lee (2020) 47 3 94.0 (83.5–98.7) 49 1 98.0 (89.4–99.9)
Yaqing Li (2020) 291 9 97.0 (94.4–98.6)
Yunbao Pan (2020) 8 14 36.4 (17.2–59.3) 13 9 59.1 (36.4–79.3) 14 8 63.6 (40.7–82.8)
Zahra Rikhtegaran Tehrani (2020) 275 25 91.7 (87.9–94.5) 280 20 93.3 (89.9–95.9) 100.0 (48.0–100.0)
Ziad Daoud (2020) 363 2 99.5 (98.0–99.9) 365 0 100 (99.0–100) 97.0 (94.0–99.0)
Jialin Xiang ((2020)/10) 13 4 76.5 (50.1–93.2)
Valentina Pecoraro (2021) 3 12 20.0 (4.0–48.0) 3 12 20.0 (4.0–48.0)
Marina Bubonja-Šonje (2021) 100 0 100.0 (96.0–100.0) 100 0 100.0 (96.0–100.0)
Bianca A. Trombetta (2021) 55 1 98.0 (90.0–100.0) 56 0 100.0 (94.0–100.0) 56 0 100.0 (94.0–100.0)
Oskar Ekelund (2021) 145 5 97.0 (92.0–99.0)
Norihito Kaku (2021) 174 0 100.0 (98.0–100.0) 172 2 99.0 (96.0–100.0)
Sérgio M. de Almeida (2021) 37 0 100.0 (91.0–100.0) 37 0 100.0 (91.0–100.0) 37 0 100.0 (91.0–100.0)
Amedeo De Nicolò (2021) 75 4 95.0 (88.0–99.0)
Dennis Souverein (2021) 218 1 100.0 (97.0–100.0) 218 1 100.0 (97.0–100.0) 218 1 100.0 (97.0–100.0)
Sophie I. Owen (2021) 86 19 82.0 (73.0–89.0) 97 98 50.0 (43.0–57.0) 85 20 81.0 (72.0–88.0)
Shiji Wu (2022) 142 0 100.0 (97.0–100.0) 142 0 100.0 (97.0–100.0)
Ismar A. Rivera-Olivero (2022) 37 3 93.0 (80.0–98.0) 40 0 100.0 (91.0–100.0)
Pooled 5,604 256 96.0 (96.0–97.0) 6,947 225 97.0 (96.0–97.0) 12,141 317 97.0 (97.0–98.0)
CLIA (n = 64 arms)
Bin Lou (2020) 298 2 99.3 (97.6–99.9) 299 1 99.7 (98.2–100)
Dachuan Lin (2020) 74 6 92.5 (84.4–97.2) 78 2 97.5 (91.3–99.7)
Wanbing Liu (2020) 268 2 99.3 (97.4–99.9) 81 0 100 (95.5–100)
Maria Infantino (2020) 59 5 92.2 (82.7–97.4) 64 0 100 (94.4–100)
Shao Lijia (2020) 50 0 100 (92.9–100) 50 0 100 (92.9–100)
Fang Hu (2020) 109 1 99.1 (95.0–100) 106 4 96.4 (91.0–99.0) 134 0 100 (97.3–100)
Charpentier, C (2020) 50 2 96.2 (86.8–99.5)
Jääskeläinen, A J (2020) 77 4 95.1 (87.8–98.6)
Ping li (2020) 126 8 94 (88.6–97.4) 133 1 99.3 (95.9–100)
Chew, K L (2020) 163 0 100 (97.8–100)
Fabrizio Bonelli (2020) 4,923 117 97.7 (97.2–98.1)
Narjis Boukli (2020) 297 3 99 (97.1–99.8)
Andrew Bryan (2020) 1,010 10 99 (98.2–99.5)
MarinaJohnson (2020) 189 5 97.4 (94.1–99.2)
Niko Kohmer (2020) 35 0 100 (90.0–100)
Z. Huang (2020) 190 4 97.9 (94.8–99.4)
Ayesha Appa (2020) 1,874 6 99.7 (99.3–99.9)
Chungen Qian (2020) 946 26 97.3 (96.1–98.2) 947 25 97.4 (96.2–98.3) 72 0 100 (95.0–100)
Marie Tré-Hardy (2020) 4 0 100 (39.8–100)
Isabel Montesinos (2020) 72 0 100 (95.0–100) 72 0 100 (95.0–100)
Julien Marlet (2020) 176 2 98.9 (96.0–99.9)
Elitza S. Theel (2020) 297 1 99.7 (98.1–100)
Massimo Pieri (2020) 40 0 100 (91.2–100) 40 0 100 (91.2–100) 374 15 96.1 (93.7–97.8)
Thomas Nicol (2020) 151 1 99.3 (96.4–100)
Morihito Takita (2020) 38 2 95 (83.1–99.4)
Raymond T (2020) 234 1 99.6 (97.7–100) 233 2 99.1 (97.0–99.9) 355 35 91 (87.7–93.7)
Justin Manalac (2020) 1,236 25 98 (97.1–98.7) 55 6 90.2 (79.8–96.3)
C. S. Lau (2020) 978 2 99.8 (99.3–100)
Yafang Wan (2020) 371 19 95.1 (92.5–97.0) 355 35 91 (87.7–93.7) 129 1 99.2 (95.8–100)
E. Catry (2020) 98 2 98 (93–99.8) 100 0 100 (96.4–100)
Li-xiang Wu (2020) 229 5 97.9 (95.1–99.3) 219 15 93.6 (89.6–96.4) 215 19 91.9 (87.6–95.0)
Jenna Rychert (2020) 99 1 99 (94.6–100)
Anja Dörschug (2020) 189 3 98.4 (95.5–99.7)
Nan wu (2020) 34 0 100 (89.7–100) 32 2 94.1 (80.3–99.3)
Shey-Ying Chen (2020) 190 4 97.9 (94.8–99.4)
Xueping Qiu (2020) 377 12 96.9 (94.7–98.4) 377 12 96.9 (94.7–98.4) 374 15 96.1 (93.7–97.8)
Hélène Haguet (2021) 75 1 98.7 (92.9–100) 76 0 100 (95.3–100)
Huihui Wang (2021) 94 94 50 (42.6–57.4)
Rasmus Strand MSc (2021) 45 5 90 (78.2–96.7) 49 1 98 (89.4–99.9)
Tania ReginaTozetto-Mendoza (2021) 92 2 97.9 (92.5–99.7)
C. S. Lau (2021) 245 3 98.8 (96.5–99.7)
Luigi Vimercati (2021) 2,117 272 88.6 (87.3–89.9) 2,341 48 98 (97.3–98.7)
Sousuke Kubo (2021) 1,000 0 100 (99.6–100) 1,000 0 100 (99.6–100)
Anna Schaffner (2020) 1,157 2 99.8 (99.4–100)
N. Davidson (2020) 130 8 94.2 (88.9–97.5)
A Cramer (2021) 25 0 100 (86.3–100)
Victoria Higgins (2021) 107 0 100 (96.6–100) 214 0 100 (98.3–100) 107 0 100 (96.6–100)
Myriam C. Weber (2020) 2,377 9 99.6 (99.3–99.8) 1,192 1 99.9 (99.5–100)
Maximilian Kittel (2020) 188 6 96.9 (93.4–98.9) 288 3 99 (97.0–99.8) 42 0 100 (91.6–100)
Christian Irsara (2021) 487 2 99.6 (98.5–100) 627 2 99.7 (98.9–100)
Yaqing Li (2020) 204 10 95.3 (91.6–97.7)
Yuki Nakano (2021) 125 19 86.8 (80.2–91.9) 144 0 100 (97.5–100)
Brad Poore (2021) 129 0 100.0 (97.0–100.0)
Valentina Pecoraro (2021) 2 13 13.0 (2.0–40.0) 2 13 13.0 (2.0–40.0)
Gabriel N Maine (2022) 302 3 99.0 (97.0–100.0)
Kotaro Aoki (2021) 677 7 99.0 (98.0–100.0)
Marina Bubonja-Šonje (2021) 99 1 99.0 (95.0–100.0)
Oskar Ekelund (2021) 149 1 99.0 (96.0–100.0)
Lau CS (2021) 248 0 100.0 (99.0–100.0)
Maria del Mar Castro (2021) 59 0 100.0 (94.0–100.0)
Robert Needle (2021) 109 2 98.0 (94.0–100.0)
Adnan Alatoom (2021) 30 0 100.0 (88.0–100.0)
Shiji Wu (2022) 142 0 100.0 (97.0–100.0) 142 0 100.0 (97.0–100.0)
Vijayalakshmi Nandakumar (2021) 189 3 98.0 (96.0–100.0)
Pooled 6,336 403 94.0 (93.0–95.0) 23,686 384 98.0 (98.0–99.0) 7,250 215 97.0 (97.0–97.0)

Ig, immunoglobulin; TP, true positive; FN, false negative; TN, true negative; FP, false positive; ELISA, enzyme linked immunosorbent assay; LFIA, lateral flow immunoassay; CLIA, chemiluminescent immunoassay.

Sensitivity and specificity by potential sources of heterogeneity

Table 4 reports the stratified meta-analyses for evaluating potential sources of heterogeneity in sensitivity and specificity. Heterogeneity was observed in all of the analyses.

Table 4.

Accuracy of COVID-19 serology tests stratified by potential sources of heterogeneity.

Subgroup IgM IgG IgM or IgG
No. of arms (studies) TP FN Pooled sensitivity (95% CI) No. of arms TP FN Pooled sensitivity (95% CI) No. of arms TP FN Pooled sensitivity (95% CI)
Time post-onset
ELISA
First week 3 80 86 48.0 (40.0–56.0) 7 704 131 84.0 (82.0–87.0) 4 445 77 85.0 (82.0–88.0)
Second week 4 212 107 66.0 (61.0–72.0) 8 491 147 77.0 (73.0–80.0) 5 482 78 86.0 (83.0–89.0)
Third week 6 925 184 83.0 (81.0–86.0) 20 2,502 245 91.0 (90.0–92.0) 2 123 2 98.0 (94.0–100.0)
Third week later 1 62 5 93.0 (83.0–98.0) 6 844 171 83.0 (81.0–85.0) 2 194 21 90.0 (85.0–94.0)
CLIA
First week 6 666 405 62.0 (59.0–65.0) 11 1,086 729 60.0 (58.0–62.0) 2 334 298 53.0 (49.0–57.0)
Second week 5 462 433 52.0 (48.0–55.0) 9 772 452 63.0 (60.0–66.0) 4 654 258 72.0 (69.0–75.0)
Third week 6 686 2,249 23.0 (22.0–25.0) 13 1,790 3,727 32.0 (31.0–34.0) 6 1,152 759 60.0 (58.0–62.0)
Third week later 5 495 238 68.0 (64.0–71.0) 6 1,159 255 82.0 (80.0–84.0) 2 467 58 89.0 (86.0–92.0)
LFIA
First week 5 109 300 27.0 (22.0–31.0) 5 119 291 29.0 (25.0–34.0) 16 1,725 1,080 61.0 (60.0–63.0)
Second week 3 169 2,723 6.0 (5.0–7.0) 3 204 2,711 7.0 (6.0–8.0) 6 501 3,027 14.0 (13.0–15.0)
Third week 12 547 474 54.0 (50.0–57.0) 12 672 698 49.0 (46.0–52.0) 9 1,192 1,329 47.0 (45.0–49.0)
Third week later 3 68 85 44.0 (36.0–53.0) 3 129 24 84.0 (78.0–90.0) 7 646 624 51.0 (48.0–54.0)
Antigen target
ELISA
Surface protein 6 449 280 62.0 (58.0–65.0) 24 2,513 592 81.0 (80.0–82.0) 8 835 148 85.0 (83.0–87.0)
Nucleocapsid protein 7 537 96 85.0 (82.0–88.0) 21 1,513 292 84.0 (82.0–85.0) 2 284 8 97.0 (95.0–99.0)
Surface and nucleocapsid proteins 5 480 336 59.0 (55.0–62.0) 13 2,490 782 76.0 (75.0–78.0) 6 629 94 87.0 (84.0–89.0)
CLIA
Surface protein 3 254 371 41.0 (37.0–45.0) 8 956 390 71.0 (69.0–73.0) 3 487 181 73.0 (69.0–76.0)
Nucleocapsid protein 0 5 464 144 76.0 (73.0–80.0) 3 421 29 94.0 (91.0–96.0)
Surface and nucleocapsid proteins 4 770 324 70.0 (68.0–73.0) 9 1,668 793 68.0 (66.0–70.0) 5 879 638 58.0 (55.0–60.0)
LFIA
Surface protein NA
Nucleocapsid protein 1 101 26 80.0 (71.0–86.0) 3 206 325 39.0 (35.0–43.0) 1 80 63 56.0 (47.0–64.0)
Surface and nucleocapsid proteins 4 211 148 59.0 (53.0–64.0) 4 218 141 61.0 (55.0–66.0) 3 231 77 75.0 (70.0–80.0)
Clinical setting
ELISA
Inpatient only 11 792 282 74.0 (71.0–76.0) 15 1,730 355 83.0 (81.0–85.0) 6 905 165 85.0 (82.0–87.0)
Outpatient 0 7 584 61 91.0 (88.0–93.0) 0
Inpatient and outpatient 6 560 104 84.0 (81.0–87.0) 14 1,769 148 92.0 (91.0–93.0) 6 1,266 139 90.0 (88.0–92.0)
No reported 10 1,083 463 70.0 (68.0–72.0) 39 5,073 1,153 81.0 (80.0–82.0) 11 1,227 288 81.0 (79.0–83.0)
CLIA
Inpatient only 10 1,282 519 71.2 (69.0,73.3) 15 2,006 548 78.5 (76.8,80.1) 7 1,757 472 78.8 (77.1,80.5)
Outpatient 0 1 123 29 0
Inpatient and outpatient 4 712 219 76.3 (73.4,79.0) 14 2,199 625 74.0 (72.0,75.9) 8 2,332 471 83.2 (81.8,84.6)
No reported 8 841 919 33.6 (31.0,36.3) 19 2,269 2,120 44.2 (42.6,45.8) 8 697 842 45.0 (43.0,48.0)
LFIA
Inpatient only 4 216 216 50.0 (45.0–55.0) 3 201 179 53.0 (48.0–58.0) 6 1,554 1,170 57.0 (55.0–59.0)
Outpatient 4 654 4,636 12.0 (11.0–13.0)
Inpatient and outpatient 5 212 107 66.0 (61.0–72.0) 8 579 613 49.0 (46.0–51.0) 7 785 797 50.0 (47.0–52.0)
No reported 21 2,031 5,411 27.0 (26.0–28.0) 20 1,946 5,187 27.0 (26.0–28.0) 17 1,472 4,952 23.0 (22.0–24.0)
Serological kit as index test (whether testing was by commercial kit or an in-house assay)
ELISA
Commercial serological kit 23 2,022 703 74.0 (73.0–76.0) 66 8,167 1,731 83.0 (82.0–83.0) 21 2,632 617 81.0 (80.0–82.0)
In-house assay 6 640 238 73.0 (70.0–76.0) 13 1,220 102 92.0 (91.0–94.0) 5 965 125 89.0 (86.0–90.0)
Unclear 0 0 0
CLIA
Commercial serological kit 20 1,697 3,510 33.0 (31.0–34.0) 43 4,790 5,427 47.0 (46.0–48.0) 18 3,153 1,565 67.0 (65.0–68.0)
In-house assay 2 1,069 212 83.0 (81.0–85.0) 4 1,493 151 91.0 (89.0–92.0) 2 949 131 88.0 (86.0–90.0)
Unclear 0 2 116 68 63.0 (56.0–70.0) 0
LFIA
Commercial serological kit 28 2,397 5,148 32.0 (31.0–33.0) 25 2,489 5,100 33.0 (32.0–34.0) 30 4,263 11,073 28.0 (27.0–29.0)
In-house assay 2 696 963 42.0 (40.0–44.0)
Unclear 4 199 700 22.0 (19.0–25.0) 4 186 830 18.0 (16.0–21.0) 4 202 414 33.0 (29.0–37.0)
Type of specimen for RT–PCR reference test
ELISA
Nasopharyngeal 11 575 296 66.0 (63.0–69.0) 27 3,796 934 80.0 (79.0–81.0) 10 1,322 418 76.0 (74.0–78.0)
Sputum, saliva, or oral, throat, or pharyngeal 7 484 132 79.0 (75.0–82.0) 17 1,426 291 83.0 (81.0–85.0) 6 837 273 75.0 (73.0–78.0)
Not reported 11 1,435 458 76.0 (74.0–79.0) 38 4,566 682 87.0 (86.0–88.0) 12 1,958 129 94.0 (93.0–95.0)
CLIA
Nasopharyngeal 7 578 2,328 20.0 (18.0–21.0) 16 1,364 2,791 33.0 (31.0–34.0) 6 1,075 397 73.0 (71.0–75.0)
Sputum, saliva, or oral, throat, or pharyngeal 6 656 246 73.0 (70.0–76.0) 8 788 283 74.0 (71.0–76.0) 6 1,253 181 87.0 (86.0–89.0)
Not reported 13 1,688 1,325 56.0 (54.0–58.0) 30 4,872 3,711 57.0 (56.0–58.0) 11 2,436 1,218 67.0 (65.0–68.0)
LFIA
Nasopharyngeal 8 992 1,366 42.0 (40.0–44.0) 8 1,004 1,272 44.0 (42.0–46.0) 13 2,180 6,808 24.0 (23.0–25.0)
Sputum, saliva, or oral, throat, or pharyngeal 9 1,020 1,301 44.0 (42.0–46.0) 9 1,124 1,305 46.0 (44.0–48.0) 8 719 5,477 12.0 (11.0–12.0)
Not reported 17 1,339 4,106 25.0 (23.0–26.0) 16 1,331 4,436 23.0 (22.0–24.0) 18 1,880 4,612 29.0 (28.0–30.0)
Subgroup IgM IgG IgM or IgG
No. of arms (studies) TN FP Pooled specificity (95% CI) No. of arms TN FP Pooled specificity (95% CI) No. of arms TN FP Pooled specificity (95% CI)
Time post-onset
ELISA
First week 3 440 34 93.0 (90.0–95.0) 7 27,47 129 96.0 (95.0–96.0) 4 726 64 92.0 (90.0–94.0)
Second week 4 432 13 97.0 (95.0–98.0) 8 1,064 35 97.0 (96.0–98.0) 5 9,861 14 100.0 (100.0–100.0)
Third week 6 3,535 18 99.0 (99.0–100.0) 20 8,177 597 93.0 (93.0–94.0) 2 306 0 100.0 (99.0–100.0)
Third week later (22–28 day) 1 109 3 97.0 (92.0–99.0) 6 2,749 81 97.0 (96.0–98.0) 2 224 3 99.0 (96.0–100.0)
CLIA
First week 6 1,392 38 97.0 (96.0–98.0) 11 9,424 159 98.0 (98.0–99.0) 2 238 22 92.0 (87.0–95.0)
Second week 5 982 29 97.0 (96.0–98.0) 9 1,376 50 96.0 (95.0–97.0) 4 427 102 81.0 (77.0–84.0)
Third week 6 1,084 290 79.0 (77.0–81.0) 13 1,838 84 96.0 (95.0–96.0) 6 939 15 98.0 (97.0–99.0)
Third week later (22–28 day) 5 910 20 98.0 (97.0–99.0) 6 1,826 30 98.0 (98.0–99.0) 2 508 15 97.0 (95.0–98.0)
LFIA
First week 5 58 42 58.0 (48.0–68.0) 5 88 9 91.0 (83.0–96.0) 16 994 52 95.0 (94.0–96.0)
Second week 3 72 12 86.0 (76.0–92.0) 3 31 24 56.0 (42.0–70.0) 6 164 30 85.0 (79.0–89.0)
Third week 12 341 58 85.0 (82.0–89.0) 12 347 135 72.0 (68.0–76.0) 9 175 52 77.0 (71.0–82.0)
Third week later (22–28 day) 2 273 2 99.0 (97.0–100.0) 2 274 1 100.0 (98.0–100.0) 7 512 20 96.0 (94.0–98.0)
Antigen target
ELISA
Surface protein 6 2,396 4 100.0 (100.0–100.0) 24 7,008 143 98.0 (98.0–98.0) 8 1,737 17 99.0 (98.0–99.0)
Nucleocapsid protein 7 1,075 32 97.0 (96.0–98.0) 21 4,889 125 98.0 (97.0–98.0) 2 9,651 14 100.0 (100.0–100.0)
Surface and nucleocapsid proteins 5 1,365 32 98.0 (97.0–98.0) 13 4,806 251 95.0 (94.0–96.0) 6 764 10 99.0 (98.0–99.0)
CLIA
Surface protein 3 508 6 99.0 (97.0–100.0) 8 1,056 87 92.0 (91.0–94.0) 3 1,516 3 100.0 (99.0–100.0)
Nucleocapsid protein 0 5 1,319 14 99.0 (98.0–99.0) 3 1,557 2 100.0 (100.0–100.0)
Surface and nucleocapsid proteins 4 774 27 97.0 (95.0–98.0) 9 6,268 144 98.0 (97.0–98.0) 2 380 34 92.0 (89.0–94.0)
LFIA
Surface protein NA
Nucleocapsid protein 1 37 3 93.0 (80.0–98.0) 3 52 20 72.0 (60.0–82.0) 1 75 4 95.0 (88.0–99.0)
Surface and nucleocapsid proteins 4 415 20 95.0 (93.0–97.0) 4 425 100 81.0 (77.0–84.0) 3 286 25 92.0 (88.0–95.0)
Clinical setting
ELISA
Inpatient only 11 2,057 70 97.0 (96.0–97.0) 15 3,964 627 86.0 (85.0–87.0) 6 1,275 3 100.0 (99.0–100.0)
Outpatient 0 7 5,641 75 99.0 (98.0–99.0) 0
Inpatient and outpatient 6 2,083 17 99.0 (99.0–100.0) 14 5,397 234 96.0 (95.0–96.0) 6 1,470 63 96.0 (95.0–97.0)
No reported 10 3,517 44 99.0 (98.0–99.0) 39 11,119 266 98.0 (97.0–98.0) 11 12,251 88 99.0 (99.0–99.0)
CLIA
Inpatient only 10 1,798 35 98.0 (97.0–99.0) 15 3,435 68 98.0 (98.0–98.0) 7 2,251 67 97.0 (96.0–98.0)
Outpatient 0 1 149 1 99.0 (96.0–100.0) 0
Inpatient and outpatient 4 949 19 98.0 (97.0–99.0) 14 8,680 170 98.0 (98.0–98.0) 8 3,065 30 99.0 (99.0–99.0)
No reported 8 967 39 96.0 (95.0–97.0) 19 4,679 172 96.0 (96.0–97.0) 8 218 108 67.0 (61.0–72.0)
LFIA
Inpatient only 4 75 47 61.0 (52.0–70.0) 3 43 14 75.0 (62.0–86.0) 6 623 53 92.0 (90.0–94.0)
Outpatient 4 247 178 58.0 (53.0–63.0)
Inpatient and outpatient 5 413 14 97.0 (95.0–98.0) 8 455 13 97.0 (95.0–99.0) 7 552 6 99.0 (98.0–100.0)
No reported 21 1,372 194 88.0 (86.0–89.0) 20 1,137 198 85.0 (83.0–87.0) 17 1,147 78 94.0 (92.0–95.0)
Serological kit as index test (whether testing was by commercial kit or an in-house assay)
ELISA
Commercial serological kit 23 6,288 127 98.0 (98.0–98.0) 66 23,800 1,176 95.0 (95.0–96.0) 21 12,676 144 99.0 (99.0–99.0)
In-house assay 6 1,510 20 99.0 (98.0–99.0) 13 2,360 51 98.0 (97.0–98.0) 5 1,566 10 99.0 (99.0–100.0)
Unclear 0 0 0
CLIA
Commercial serological kit 20 2,370 359 87.0 (86.0–88.0) 43 12,762 393 97.0 (97.0–97.0) 18 4,452 174 96.0 (96.0–97.0)
In-house assay 2 1,285 6 100.0 (99.0–100.0) 4 2,705 39 99.0 (98.0–99.0) 2 751 15 98.0 (97.0–99.0)
Unclear 0 2 248 2 99.0 (97.0–100.0) 0
LFIA
Commercial serological kit 28 1,841 200 90.0 (89.0–91.0) 25 1,567 194 89.0 (87.0–90.0) 30 2,529 309 89.0 (88.0–90.0)
In-house assay 2 478 23 95.0 (93.0–97.0)
Unclear 4 27 61 31.0 (21.0–41.0) 4 47 31 60.0 (49.0–71.0) 4 40 6 87.0 (74.0–95.0)
Type of specimen for RT–PCR reference test
ELISA
Nasopharyngeal 11 1,073 37 97.0 (95.0–98.0) 27 10,648 346 97.0 (97.0–97.0) 10 1,412 97 94.0 (92.0–95.0)
Sputum, saliva, or oral, throat, or pharyngeal 7 875 26 97.0 (96.0–98.0) 17 7467 616 92.0 (92.0–93.0) 6 510 60 89.0 (87.0–92.0)
Not reported 11 5,866 71 99.0 (98.0–99.0) 38 13,488 339 98.0 (97.0–98.0) 12 13,642 57 100.0 (99.0–100.0)
CLIA
Nasopharyngeal 7 830 294 74.0 (71.0–76.0) 16 5,900 122 98.0 (98.0–98.0) 6 699 28 96.0 (94.0–97.0)
Sputum, saliva, or oral, throat, or pharyngeal 6 1,135 22 98.0 (97.0–99.0) 8 2,671 23 99.0 (99.0–99.0) 6 2,042 124 94.0 (93.0–95.0)
Not reported 13 1,954 55 97.0 (96.0–98.0) 30 10,332 322 97.0 (97.0–97.0) 11 2,779 47 98.0 (98.0–99.0)
LFIA
Nasopharyngeal 8 785 79 91.0 (89.0–93.0) 8 743 39 95.0 (93.0–96.0) 13 1,514 215 88.0 (86.0–89.0)
Sputum, saliva, or oral, throat, or pharyngeal 9 885 103 90.0 (87.0–91.0) 9 844 49 95.0 (93.0–96.0) 8 950 196 83.0 (81.0–85.0)
Not reported 17 645 130 83.0 (80.0–86.0) 16 513 160 76.0 (73.0–79.0) 18 643 65 91.0 (88.0–93.0)

Subgroup analysis of the timing of sample collection in relation to symptom onset

The average sensitivity across all of the included studies for ELISA-tested IgG, IgM and IgG/IgM showed low sensitivity during the first week after the onset of symptoms, after which they increased in the second week and reached their highest values beyond 3 weeks. For the ELISAs, sensitivity estimates were higher in the third week or later after symptom onset (ranging from 83.0 to 90.0%). In contrast, for the CLIAs, pooled sensitivity was lower in the third week (<30%); for the LFIAs, pooled sensitivity was lower in the second week (<10%) after symptom onset. Very few studies have evaluated tests beyond 35 days to estimate accuracy. Data on specificity, as stratified by timing, showed that the pooled data were highest in the second week. Specificity was higher at least 2 weeks after symptom onset (ranging from 98.0 to 98.0%) than within the first week (ranging from 96.0 to 97.0%). For the ELISA test method, the pooled specificity of 99% (ranging from 99 to 100%) was high when the measured time post-onset was in the second week. For the CLIA and FLIA test methods, the pooled specificity was high when measured time post-onset was in the third week later (ranging from 97 to 99%) (Table 4).

Subgroup analysis of test technology type

Point estimates for the pooled sensitivity and specificity were higher when the N protein was used. A subgroup meta-analysis showed that tests using the N antigen (ranging from 77 to 80%) were more sensitive than with the use of S protein (ranging from 66.0 to 68.0.0%) antigen tests. Moreover, IgG-based serological assays that used the N antigen were more sensitive than IgG-based serological assays that used the S antigen. For the ELISAs, specificity was higher when the nucleocapsid protein was used; however, this was not the case for the LFIAs or CLIAs. For the CLIAs, specificity and sensitivity were higher from reported studies that used the nucleocapsid proteins (ranging from 99 to 100%) (Table 4).

Subgroup analysis of setting (outpatient vs. inpatient)

For the ELISAs, point estimates for pooled sensitivity were higher when estimates at the sample level for both inpatients and outpatients were included, in which case the sensitivity was 90% (ranging from 89 to 91%). For the LFIAs, pooled specificity was higher when estimates at the sample level for both inpatient and outpatient were included, in which case the specificity was 98% (ranging from 97 to 98%). Among the three test methods, point estimates for pooled sensitivity and specificity were higher when estimates at the sample level included both inpatients and outpatients (Table 4).

Subgroup analysis of serological kits as index tests (whether testing was performed by using commercial kits or an in-house assay)

Both in-house and commercial kits are the preferred molecular tests being used worldwide in the COVID-19 diagnosis. We compared pooled sensitivity and specificity across subgroup according to serological kit as index test (whether testing was by commercial kit or an in-house assay). For all three of the test methods, point estimates of sensitivity and specificity were higher for in-house assays vs. commercial kits. The pooled sensitivity was higher for in-house assays (ranging from 78 to 79%) than for commercial kits (ranging from 47 to 48%). The pooled specificity was higher for in-house assays (ranging from 98 to 99%) than for commercial kits (ranging from 96 to 96%) (Table 4).

Subgroup analysis of the type of specimen used for the RT–PCR reference test

For the ELISA and CLIA test methods, pooled specificity and sensitivity were high when the types of specimens that were used for the RT–PCR were sputum, saliva, oral, throat or pharyngeal samples. However, when the sample was nasopharyngeal, the pooled sensitivity and specificity were high, as indicated by the LFIA test method (Table 4).

The accuracy of serological tests world map for COVID-19

We pooled the sensitivity and specificity of COVID-19 serological tests that are used worldwide. For the ELISA, pooled sensitivity was higher in Canada (100%) than in other areas; For the CLIA, pooled sensitivity was higher in Croatia (97%) than in other areas (Supplementary Figures S5S7). Among these three serological tests, ELISA exhibited higher sensitivity (ranging from 50 to 100%) and higher specificity (ranging from ≥73–100%). For the CLIA, Italy, Switzerland and Singapore had lower sensitivities (< 30%) (Supplementary Table S3). Among the three test methods, point estimates for pooled specificity were higher in Latin America (ranging from 99.0 to 100%) (Supplementary Figures S4S9, Supplementary Table S3).

Discussion

In this systematic review and meta-analysis, we found that ELISA and CLIA methods performed better in terms of sensitivity than the LFIA method, thus indicating that viral infections can lead to false-positive results for the LIFA method. For each test method, the type of immunoglobulin being measured (IgM, IgG or both) was associated with diagnostic accuracy, and sensitivities were consistently higher with IgG than with IgM. Moreover, IgG-IgM-based CLIA tests exhibited the best overall diagnostic test accuracy. Moreover, pooled specificities of each test method were high. Pooled sensitivities and specificities were higher with in-house assays vs. commercial kits and in the third week or later, compared with the first and second weeks after symptom onset. Additionally, point estimates for pooled sensitivity and specificity were higher when estimates at the sample level were both inpatient and outpatient; therefore, serological tests are able to detect lower antibody levels that are likely observed with milder and asymptomatic COVID-19 disease.

Research implications

1. For all three of the methods, the LFIA method had lower sensitivity than the ELISA or CLIA methods for IgM (similar data were available for IgG and IgM/IgG). For the LFIAs, pooled sensitivity was lowest in the second week of symptom onset and highest in the first week. These observations can provide recommendations to the World Health Organization for improving test accuracy when using LFIA serological tests. Given the poor performances of the current LFIA devices (7, 16), LFIA tests for COVID-19 in the second week of symptom onset (with an average sensitivity of 9%) will be falsely identified as not being positive for infection. In addition, sensitivity estimates are likely to increase in the first week, compared with other time points of sample collection. Our time-stratified analyses suggest that LFIA seems to be a better choice (in terms of sensitivity) at the first week of sample collection, in relation to symptom onset.

2. For all three of the test methods, pooled sensitivities and specificities were higher with in-house assays vs. commercial kits. These findings are expected, given that the pooled sensitivities were lower with the commercial kits than with in-house assays (7). Point estimates of pooled sensitivity were lower for commercial kits vs. in-house assays, for all three methods, with the strongest difference seen for LFIAs, where the sensitivity of commercial kits was 28.0% sensitivity and 89.0% specificity with IgM or IgG. For commercial kits based LFIA, the sensitivity was found to be below 50% and higher quality clinical studies assessing the diagnostic accuracy of commercial kits based LFIA are urgently needed.

3. Sensitivity varied with the time since the onset of symptoms and technology test methods. Our findings should give pause to governments that are contemplating the use of serological tests. For example, if LFIAs are applied to a population in the second week after the onset of symptoms, the average sensitivity of the test may be 9%; thus, only 9 patients out of 100 true positive patients can be detected. Serological tests are likely to have a useful role in detecting previous COVID-19 infections if they are used at 15 or more days after the onset of symptoms, except with estimated pooled specificities using CLIAs and LFIAs test methods, which are more suitable for use at 7 days after the onset of symptoms. Overall, the type of sample should be collected with consideration of the timing of the infection. It is necessary to perform the correct test at the correct time in the sample collection process, in order to avoid misdiagnoses of asymptomatic patients who are negative for serological tests.

4. Sensitivity has mainly been evaluated in hospitalized patients (7, 10); therefore, it is unclear whether the tests are able to detect lower antibody levels that are likely observed with milder and asymptomatic COVID-19 disease. Few studies have solely evaluated outpatient sensitivity accuracy. Point estimates for pooled sensitivity and specificity were higher when estimates at the sample level included both inpatients and outpatients. Our findings support the use of serological tests that are applied to people with mild symptoms who were not hospitalized, thus reducing variability in the estimates and enhancing generalizability.

5. There was little clear evidence of differences in specificity between the technology types. Specifically, all of the tests displayed high specificities. Within each class of immunoglobulin, specificity was lowest for the IgM-based CLIA tests.

6. Generally, IgG-based serological tests demonstrated a better choice in terms of sensitivity than IgM-based serological assays in each respective test method. IgG-based tests may be a safer choice at this stage of the pandemic. Low IgM antibody concentrations could potentially be explained by the fact that, immediately after a person is infected, antibodies may not have been developed yet; additionally, if it is too late after a person has been infected, IgM antibodies may have decreased or disappeared (17). The nucleocapsid protein and surface protein were used for detecting IgM and IgG antibodies, and their diagnostic feasibilities were evaluated. A subgroup meta-analysis showed that nucleocapsid antigen-based IgG serological assays are more sensitive than S antigen-based IgG serological assays that use the S antigen, thus indicating that combined IgG/IgM test antigen target nucleocapsid protein-based CLIA tests have the best overall diagnostic test accuracy.

Comparison to previous studies

The sensitivities of all of the serological assays varied widely across the studies. Similar to other meta-analyses (7, 16, 18), the LFIA method had lower sensitivities than the CLIA and ELISA methods within each antibody class. CLIA and ELISA may be a safer choice at this stage of the pandemic. In addition, similar to other meta-analyses (17), IgM-based serological assays had the lowest sensitivities, compared with IgG-based serological tests, in each respective test method. From this study, we showed that IgG-IgM-based CLIA tests had a higher pooled sensitivity than the ELISA and LFIA tests. Moreover, it must be noted that a meta-analysis by Vengesai et al. (16) found that IgG-IgM-based ELISA tests have the best overall diagnostic test accuracy; however, in that review, they did not estimate the pooled sensitivity of IgG-IgM-based CLIA, due to the limited number of studies.

Few studies have evaluated tests beyond 35 days to estimate accuracy. For ELISAs, sensitivity estimates were higher in the third week or later after the onset of symptoms (ranging from 88 to 90%). In contrast, for the CLIAs, pooled sensitivity was lower in the third week (< 35%); For LFIAs, pooled sensitivity was lower in the second week (< 10%) after symptom onset. These findings differ from those of previous studies, in which sensitivity estimates were lowest in the first week of symptom onset and highest in the third week or later (7, 10). These observations argue against the use of serological tests for COVID-19 that exhibit higher sensitivity when performed later during the course of the disease.

A subgroup meta-analysis showed that tests using the nucleocapsid antigen were more sensitive than surface antigen tests in each immunoglobulin (IgM, IgG or both) test method. The pooled sensitivity results are in agreement with other meta-analyses that demonstrated that IgG-based serological assays that use the N antigen are more sensitive than IgG-based serological assays that use the S antigen (17). However, it must be noted that a meta-analysis by Liu et al. (19) showed that the S antigen is more sensitive than IgM-based serological assays that used N antigen tests. Thus, there is a need for more research concerning a higher sensitivity and earlier immune response to the nucleocapsid antigen.

Strengths and limitations of this review

Our review had several strengths. For example, our review involved two independent reviewers who systematically assessed potential sources of bias. Additionally, the entire search strategy and data analysis process were relatively standardized. Moreover, we included 134 published articles on SARS-CoV-2 infections that were defined by RT–PCR because a considerable amount of new research is being published in this field. The advantages of large studies and large sample sizes allow researchers to magnify the bias associated with error, which can result from sampling or study design. Another strength of our review was that the study was conducted using in-depth subgroup meta-analyses to evaluate potential sources of heterogeneity in sensitivity and specificity, which reduces variability in the estimates and enhances diagnostic accuracy.

Our study also had some limitations. For example, we did not pool sensitivity and specificity for measurements of IgA or total immunoglobulin levels, due to small numbers. Another limitation was that we did not search for studies from individuals who were not suspected of having COVID-19 or specimens from individuals with COVID-19 symptoms and a negative RT–PCR result for SARS-CoV-2.

Conclusions

Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all of the patients), but this was not followed by a rapid decline in viral load (20). There is an urgent need for an effective and accurate diagnostic method to limit the spread of the COVID-19 infection. At present, rapid antigen or antibody tests, immunoenzymatic serological tests and molecular tests based on RT–PCR are the most widely used and validated techniques worldwide (21). We have found major weaknesses in the evidence base for serological tests for COVID-19. It is necessary to take into account not only the right test method (ELISAs, LFIAs, or CLIAs) but also the correct time from the onset of symptoms and from the correct biological sample for a successful outcome of the diagnostic test. Due to the limitations of serological tests, other techniques, including isothermal nucleic acid amplification techniques, clusters of regularly interspaced short palindromic repeats/Cas (CRISPR/Cas)-based approaches or digital PCR methods, should be quickly approved to provide guidance for a correct diagnosis of COVID-19.

Author contributions

XZ and RD: drafting and revision of the manuscript for content, including medical writing for content, analysis or interpretation of data, and major role in the acquisition of data. FG, XW, YD, RC, and ML: major role in the acquisition of data. CT and LL: study concept or design. All authors contributed to the article and approved the submitted version.

Funding

This study was supported by the National Natural Science Foundation of China (NSFC)/82205245 to XZ, NSFC/82174479 to CT, and NSFC/82174527 and the special project of Lingnan Modernization of Traditional Chinese Medicine in 2019 Guangdong Provincial R&D Program (No. 2020B1111100008) to LL.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh.2022.923525/full#supplementary-material

Supplementary Figure S1

Visual inspection of summary ROC curves by test method and antibody class.

Supplementary Figure S2

Meta-analytical estimates of sensitivity (with 95%) by serological test method and antibody class.

Supplementary Figure S3

Meta-analytical estimates of specificity (with 95%) by serological test method and antibody class.

Supplementary Figure S4

Sensitivity of ELISA around the world.

Supplementary Figure S5

Sensitivity of CLIA around the world.

Supplementary Figure S6

Sensitivity of LFIA around the world.

Supplementary Figure S7

Specificity of ELISA around the world.

Supplementary Figure S8

Specificity of CLIA around the world.

Supplementary Figure S9

Specificity of LFIA around the world.

Supplementary Table S1

The included study individual QUADAS-2 evaluations.

Supplementary Table S2

Report the PubMed ID for each included study.

Supplementary Table S3

The accuracy of serological tests for COVID-19 around the world.

References

  • 1.Sidiq Z, Hanif M, Dwivedi KK, Chopra KK. Benefits and limitations of serological assays in COVID-19 infection. Indian J Tuberc. (2020) 67:S163–66. 10.1016/j.ijtb.2020.07.034 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Pau AK, Aberg J, Baker J, Belperio PS, Coopersmith C, Crew P, et al. Convalescent plasma for the treatment of COVID-19: perspectives of the national institutes of health COVID-19 treatment guidelines panel. Ann Intern Med. (2021) 174:93–5. 10.7326/M20-6448 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med. (2020) 382:1177–79. 10.1056/NEJMc2001737 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Winichakoon P, Chaiwarith R, Liwsrisakun C, Salee P, Goonna A, Limsukon A, et al. Negative nasopharyngeal and oropharyngeal swabs do not rule out COVID-19. J Clin Microbiol. (2020) 58:e00297-20. 10.1128/JCM.00297-20 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Kucirka LM, Lauer SA, Laeyendecker O, Boon D, Lessler J. Variation in false-negative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Ann Intern Med. (2020) 173:262–67. 10.7326/M20-1495 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Guo L, Ren L, Yang S, Xiao M, Chang D, Yang F, et al. Profiling early humoral response to diagnose novel coronavirus disease (COVID-19). Clin Infect Dis. (2020) 71:778–85. 10.1093/cid/ciaa310 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Bastos ML, Tavaziva G, Abidi SK, Campbell JR, Haraoui L-P, Johnston JC, et al. Diagnostic accuracy of serological tests for COVID-19: systematic review and meta-analysis. BMJ. (2020) 370:m2516. 10.1136/bmj.m2516 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Chen M, Qin R, Jiang M, Yang Z, Wen W, Li J. Clinical applications of detecting IgG, IgM or IgA antibody for the diagnosis of COVID-19: A meta-analysis and systematic review. Int J Infect Dis. (2021) 104:415–22. 10.1016/j.ijid.2021.01.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Boger B, Fachi MM, Vilhena RO, Cobre AF, Tonin FS, Pontarolo R. Systematic review with meta-analysis of the accuracy of diagnostic tests for COVID-19. Am J Infect Control. (2021) 49:21–9. 10.1016/j.ajic.2020.07.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Deeks JJ, Dinnes J, Takwoingi Y, Davenport C, Spijker R, Taylor-Phillips S, et al. Antibody tests for identification of current and past infection with SARS-CoV-2. Cochrane Database Syst Rev. (2020) 6:CD013652. 10.1002/14651858.CD013652 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Vandenberg O, Martiny D, Rochas O, van Belkum A, Kozlakidis Z. Considerations for diagnostic COVID-19 tests. Nat Rev Microbiol. (2021) 19:171–83. 10.1038/s41579-020-00461-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. (2009) 339:b2700. 10.1136/bmj.b2700 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Forero DA, Lopez-Leon S, González-Giraldo Y, Bagos PG. Ten simple rules for carrying out and writing meta-analyses. PLoS Comput Biol. (2019) 15:e1006922. 10.1371/journal.pcbi.1006922 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deels JJ, Reitsma JB, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. (2011) 155:529–36. 10.7326/0003-4819-155-8-201110180-00009 [DOI] [PubMed] [Google Scholar]
  • 15.Savović J, Weeks L, Sterne JAC, Turner L, Altman DG, Moher D, et al. Evaluation of the Cochrane Collaboration's tool for assessing the risk of bias in randomized trials: focus groups, online survey, proposed recommendations and their implementation. Syst Rev. (2014) 3:37. 10.1186/2046-4053-3-37 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Vengesai A, Midzi H, Kasambala M, Mutandadzi H, Mduluza-Jokonya TL, Rusakaniko S, et al. A systematic and meta-analysis review on the diagnostic accuracy of antibodies in the serological diagnosis of COVID-19. Syst Rev. (2021) 10:155. 10.1186/s13643-021-01689-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Kontou PI, Braliou GG, Dimou NL, Nikolopoulos G, Bagos PG. Antibody Tests in detecting SARS-CoV-2 infection: a meta-analysis. Diagnostics. (2020) 10:319. 10.3390/diagnostics10050319 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Berger RS, Mandel EB, Hayes TJ, Grimwood RR. Minocycline staining of the oral cavity. J Am Acad Dermatol. (1989) 21:1300–1. 10.1016/S0190-9622(89)80309-3 [DOI] [PubMed] [Google Scholar]
  • 19.Liu W, Liu L, Kou G, Zheng Y, Ding Y, Ni W, et al. Evaluation of nucleocapsid and spike protein-based enzyme-linked immunosorbent assays for detecting antibodies against SARS-CoV-2. J Clin Microbiol. (2020) 58:e00461-20. 10.1128/JCM.00461-20 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Wölfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Müller MA, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. (2020) 581:465–69. 10.1038/s41586-020-2196-x [DOI] [PubMed] [Google Scholar]
  • 21.Falzone L, Gattuso G, Tsatsakis A, Spandidos DA, Libra M. Current and innovative methods for the diagnosis of COVID19 infection (Review). Int J Mol Med. (2021) 47:100. 10.3892/ijmm.2021.4933 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Figure S1

Visual inspection of summary ROC curves by test method and antibody class.

Supplementary Figure S2

Meta-analytical estimates of sensitivity (with 95%) by serological test method and antibody class.

Supplementary Figure S3

Meta-analytical estimates of specificity (with 95%) by serological test method and antibody class.

Supplementary Figure S4

Sensitivity of ELISA around the world.

Supplementary Figure S5

Sensitivity of CLIA around the world.

Supplementary Figure S6

Sensitivity of LFIA around the world.

Supplementary Figure S7

Specificity of ELISA around the world.

Supplementary Figure S8

Specificity of CLIA around the world.

Supplementary Figure S9

Specificity of LFIA around the world.

Supplementary Table S1

The included study individual QUADAS-2 evaluations.

Supplementary Table S2

Report the PubMed ID for each included study.

Supplementary Table S3

The accuracy of serological tests for COVID-19 around the world.


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