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Review 1: "SARS-CoV-2 serological tests can generate false positive results for samples from patients with chronic inflammatory diseases"

This potentially reliable study suggests certain serologic assays for viral antibodies may have increased false-positives in patients with chronic inflammatory diseases. Additional independent verification in well-defined cohorts is needed.

Published onJan 15, 2021
Review 1: "SARS-CoV-2 serological tests can generate false positive results for samples from patients with chronic inflammatory diseases"
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SARS-CoV-2 serological tests can generate false positive results for samples from patients with chronic inflammatory diseases
Description

Abstract Objectives Patients with chronic inflammatory diseases are often treated with immunosuppressants and therefore are of particular concern during the SARS-CoV-2 pandemic. Serological tests will improve our understanding of the infection and immunity in this population, unless the tests give false positive results. The aim of this study was to evaluate the specificity of SARS-Cov-2 serological assays with samples from patients with chronic inflammatory diseases collected before April 2019, thus defined as negative.Methods Samples from patients with multiple sclerosis (MS, n=10), rheumatoid arthritis (RA, n=47) with or without rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibodies (anti-CCP2) and RF +/- systemic lupus erythematosus (SLE, n=10), were tested with 17 commercially available lateral flow assays (LFA), two ELISA kits and one in-house developed multiplex bead-based assay.Results Six LFA and the in-house IgG assay gave the correct negative results for all samples. However, the majority of assays (n=13), gave false positive signal with samples from patients with RA and SLE. This was most notable in RF positive RA samples. MS samples did not give any false positive in any of the assays.Conclusion The majority of the verified serological assays were sensitive to interfering antibodies in samples from patients with chronic inflammatory diseases and therefore may have poor specificity in this context. For these patients, the risk of false positivity should be considered when interpreting results of the SARS-CoV-2 serological assays.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review:

This work provides insight into one of the populations known to have higher rates of serology interference, often due to the presence of RF.  The authors have a well-defined cohort of samples from patients with SLE, RA, and MS which they screen on 17 lateral flow assays (LFAs), two ELISA based assays, and an internal multiplex assay.  Independent verification of SARS-CoV-2 serologic assays is important and information in well-defined cohorts with possible interferences is needed.  Obtaining such cohorts from “pre-SARS-CoV-2” is difficult.  LFAs are of particular interest in epidemiologic studies for their ease of implementation and portability, and this work suggests that there may be significant bias in using some of these assays in isolation in populations with reasonable prevalence of chronic inflammatory diseases.  This work supports the current understanding of LFA serologic tests and the known increase in serologic interference from patients with chronic inflammatory diseases.

Some considerations for this work: 

·       Training and interpretation information about lateral flow operators would be helpful as point of care test interpretation varies between operators.  (eg - Were these clinical lab technicians accustomed to lateral flow interpretation or newly trained operators?)

·       Are all of these LFAs CE marked or otherwise approved by a regulatory agency? How were they chosen?

·       Pg 9: “Due to insufficient sample volume, these ELISA tests could not be verified as extensively as the other tests (supplementary table 1).”  Can the authors clarify what “as extensively” means? (eg – 40/47 RA samples were assessed)

·       There is some data to suggest that the presence of neutralizing antibodies to SARS-CoV-2 may correlate with possible immunity.  There is still a paucity of information on how neutralizing antibodies from PRNT correlate with currently available clinical serologic assays, particularly qualitative lateral flow assays.  Some caution should be used in over-interpreting the current uses of SARS-CoV-2 serologic testing, specifically as regards claims on immunity. 

·       This paper supports the use of confirmation testing in cases were LFA will be used for screening.  Laboratory based serologic assays, such as the multiplex assay developed by the authors, appear to have fewer specificity issues, even in this specialized population and would therefore be useful in orthogonal testing of positive samples.

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