Harritshoej 2021 [A].
Study characteristics | |||
Patient Sampling | Purpose: To diagnose convalescent SARS‐CoV‐2 infection Design: Multiple group study to assess sensitivity and specificity: [1] Convalescent patients with previous SARS‐CoV‐2 infection (n = 150); [2] Pre‐pandemic healthy controls (for determination of clinical sensitivity); [3] Pre‐pandemic patients with auto‐immune diseases and acute viral infections (for determination of cross‐reactivity). NB: the same set of PCR+ samples were tested across all assays, however different control sample sets were tested across assays and laboratories with minimum overlap, i.e. specificities were not from head to head comparisons. Recruitment: [1] A total of 3692 individuals were contacted via public secure mail and 639 persons responded. Only the first 150 consecutively collected serum samples from 3 May 2020 were chosen without any further selection. [2] and [3] Not stated Prospective or retrospective: Retrospective Sample size: Total sample size unclear (150 COVID cases) of which 123 samples with time pso > 21 days were eligible for our review Further detail: No further details on exclusions Inclusion: [1] convalescent patients in the Capital Region of Denmark with a confirmed SARS‐CoV‐2 NAAT result that were identified in the Danish Microbiology Database from February 2020 to April 2020 that were contacted and responded. [2] Archived plasma samples from regional pre‐COVID‐19 blood donations drawn during the influenza seasons of 2017–2018 and 2018–2019 [3] patients with unspecified auto‐immune diseases or archived local samples from patients with acute infections of cytomegalovirus (CMV) or Epstein‐Barr virus (EBV) or other acute viral respiratory infections (respiratory syncytial virus, influenza A and B viruses, and adenovirus) based on positive IgM serology obtained prior to January 2020 |
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Patient characteristics and setting | Setting: Convalescent samples (hospitalised and non‐hospitalised) Location: Patients were recruited from Capital Region of Denmark based on the Danish Microbiology Database. Country: Denmark Dates: Diagnosis was made from February 2020 to April 2020. Subsequently the samples were obtained from 3 May 2020 Symptoms and severity: Available for 149 patients only: No symptoms (n = 6, 4%); Mild (at home, well) (n = 37, 24.8%); Moderate (home, bedridden) (n = 75, 50.3%); Severe (hospitalised) (n = 2, 1.3%); Critical (assisted ventilation) (n = 29, 19.5%). Demographics: Median age (q1‐q3) = 54 (43‐64), range = 18‐83 years; male (n = 52), female (n = 97) [*1 missing value] Exposure history: Not reported Non‐Covid group 1: [2] Pre‐pandemic healthy controls (for determination of clinical sensitivity) Source: Archived plasma samples from regional pre‐COVID‐19 blood donations drawn during the influenza seasons of 2017–2018 and 2018–2019 Characteristics: Unclear (healthy blood donors) Non‐Covid group 2: [3] Pre‐pandemic patients with auto‐immune diseases and acute viral infections (for determination of cross‐reactivity) Source: Samples obtained before January 2020 Characteristics: Patients with unspecified auto‐immune diseases (n = 10 to 131) [10 samples were pooled and tested across all assays. The non‐pooled samples were tested in selected assays] Patients with acute infections of cytomegalovirus (CMV) or Epstein‐Barr virus (EBV) or other acute viral respiratory infections (respiratory syncytial virus, influenza A and B viruses, and adenovirus) based on positive IgM serology (n = 10 to 37) |
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Index tests | Test name: A] Wantai ELISA Total‐Ab assay; B] Ortho CD Vitros IgG assay; C] Siemens Atellica Total‐Ab assay; D] Roche Elecsys Total‐Ab assay; E] YHLO iFlash IgG or IgM assay; F] Abbott Architect IgG assay; G] Abbott Alinity IgG assay; H] Euroimmun ELISA IgG assay; I] Snibe Maglumi IgG/IgM assay; J] DiaSorin Liaison XL IgG assay; K] Wantai ELISA IgM assay; L] Ortho CD Vitros Total‐Ab assay; M] Siemens Vista Total‐Ab assay; Manufacturer: [A] and [K] Wantai, Beijing, China; [B] and [L] Ortho Clinical Diagnostics, Pencoed, UK; [C] and [M] Siemens Healthcare, Tarrytown, NY, USA; [D] Roche Diagnostics, Mannheim, Germany; [E] YHLO Biotechnology, Shenzhen, China; [F] Abbott, Abbott Park, IL, USA; [H] Euroimmun, Lubeck, Germany; [I] Snibe, Shenzhen, China; [J] DiaSorin, Saluggia, Italy; Antibody: [A, C, D, L, M] Total‐Ab; [B, E, F, G, H, J] IgG [E, I, K] IgM; Antigen target: [A, C, K, M] RBD; [D, F, G] N‐based; [E, I] N‐, S‐based [B,H.J.L] S‐based Evaluation setting: Designed and performed as laboratory Test method: [A, H, K] ELISA; [B, C, , E, F, G, I, J] CLIA Timing of samples: PSO: 0‐7 (n = 0); > 7‐14 (n = 7); > 14‐21 (n = 13); > 21‐42 (n = 49); > 42 (n = 71); Unknown (n = 10) Corrected data from corresponding author say 123 samples > 21 days pso. Samples used: [1] Serum; [2] Plasma; [3] Not stated Test operator: Experienced technicians from 16 participating laboratories Definition of test positivity: According to manufacturers' guidelines in all tests except CUH‐NOVO test, where ROC analysis (prioritising sensitivity) was used to define positivity: [A, B, K, L] Negative, < 1.1 (S/CO); Positive >= 1.1 (S/CO); [C, D] Negative, < 1.0 COI; positive >= 1.0 COI; [E] Negative, < 10 AU/mL (IgG), < 8 AU/mL (IgM); Positive >= 10 AU/mL (IgG), >= 8 AU/mL (IgM); [F, G] Negative, < 1.4 (S/C); Positive >= 1.4 (S/C); [H] Negative, < 0.8; Borderline, >= 0.8 to < 1.1; Positive >= 1.1; [I] Negative, < 1.0; Positive >= 1.0; [J] Negative, < 12 AU/mL; Equivocal, 12‐15 AU/mL; Positive >= 15 AU/mL; [M] Negative, < 1000 QU; Positive >= 1000 QU; Blinding reported: Unclear Threshold predefined: According to manufacturers' guidelines in all tests except CUH‐NOVO test, where ROC analysis (prioritising sensitivity) were used to define positivity |
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Target condition and reference standard(s) | Reference standard: SARS‐CoV‐2 PCR, no further details Samples used: Not reported Timing of reference standard: Not reported Blinded to index test: Yes Incorporated index test: No Definition of non‐COVID cases: [2] and [3] Pre‐pandemic Samples used: [2] and [3] Pre‐pandemic Timing of reference standard: [2] and [3] Pre‐pandemic Blinded to index test: Yes, prior to index test Incorporated index test: no |
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Flow and timing | Time interval between index and reference tests: Time from positive PCR:
0‐7 (n = 1);
> 7‐14 (n = 15);
> 14‐21 (n = 22);
> 21‐42 (n = 90);
> 42 (n = 21);
Unknown (n = 1). All patients received same reference standard: No Missing data: Yes (see numbers in Tabl 3) Uninterpretable results: Not reported Indeterminate results: Borderline results of Euroimmun ELISA [K] and DiaSorin Liaison XL [M] assays were interpreted as negative. Unit of analysis: Patients (for group [3], 10 samples were pooled and tested across all assays) |
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Comparative | |||
Notes | Funding: The development of the CUH‐NOVO SARS‐CoV‐2 total‐Ab ELISA was financially supported by grants from the Carlsberg Foundation (CF20‐0045) and the Novo Nordisk Foundation (205A0063505). Publication status: Published article Source: Journal of Clinical Microbiology Author COI: R. B. Dessau reported personal fees from a Roche Diagnostics advisory board meeting in 2018 outside this work. All other authors declared no competing interests. |
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Methodological quality | |||
Item | Authors' judgement | Risk of bias | Applicability concerns |
DOMAIN 1: Patient Selection | |||
Was a consecutive or random sample of patients enrolled? | Unclear | ||
Was a case‐control design avoided? | No | ||
Did the study avoid inappropriate exclusions? | Unclear | ||
Did the study avoid inappropriate inclusions? | No | ||
Could the selection of patients have introduced bias? | High risk | ||
Are there concerns that the included patients and setting do not match the review question? | High | ||
DOMAIN 2: Index Test (All tests) | |||
DOMAIN 2: Index Test (Antibody tests) | |||
Were the index test results interpreted without knowledge of the results of the reference standard? | Unclear | ||
If a threshold was used, was it pre‐specified? | Yes | ||
Could the conduct or interpretation of the index test have introduced bias? | Unclear risk | ||
Are there concerns that the index test, its conduct, or interpretation differ from the review question? | Unclear | ||
DOMAIN 3: Reference Standard | |||
Is the reference standards likely to correctly classify the target condition? | Yes | ||
Were the reference standard results interpreted without knowledge of the results of the index tests? | Yes | ||
The reference standard does not incorporate the index test | Yes | ||
Could the reference standard, its conduct, or its interpretation have introduced bias? | Low risk | ||
Are there concerns that the target condition as defined by the reference standard does not match the question? | High | ||
DOMAIN 4: Flow and Timing | |||
Was there an appropriate interval between index test and reference standard? | Unclear | ||
Did all patients receive the same reference standard? | No | ||
Were all patients included in the analysis? | Yes | ||
Did all participants receive a reference standard? | No | ||
Were results presented per patient? | Yes | ||
Could the patient flow have introduced bias? | High risk |