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. 2022 Nov 17;2022(11):CD013652. doi: 10.1002/14651858.CD013652.pub2

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
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)
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
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
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)
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.
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