Commentary on Positive Syphilis Serologies after Intravenous Immunoglobulin Treatment: A Diagnostic Confusion That Needs Emphasis

This case highlights the impact of intravenous immunoglobulin (IVIg) interference on laboratory testing. IVIg is a therapeutic antibody product derived from pools of thousands of donors with multiple clinical indications. IVIg interference is most commonly implicated with serological assays, but there are multiple laboratory tests that have been described to be impacted by IVIg administration including but not limited to sodium, troponin, antiglobulin testing (both direct and indirect), lymphocyte count, erythrocyte sedimentation rate, and creatinine kinase. Further, IVIg also may cause in vivo hemolysis in some patients, potentially impacting numerous analytes. Of note, the package inserts for several formulations of IVIg simply state that various passively transferred antibodies in immunoglobulin preparations may lead to interference with and misinterpretation of the results of serologic testing.

As the authors point out, there have only been a handful of cases published in which IVIg administration has resulted in a false-positive syphilis test. Similarly, for other serologic assays there are multiple case reports of false-positive results but limited studies assessing the frequency with which an interference occurs. Of note, 12 208 Medicare patients received IVIg in the US alone in 2020, up by almost 30% from 2014 (1). Further, the number of diseases in which IVIg is used off-label continues to grow in parallel, implying that the frequency of IVIg interference is likely underreported. As evidence of this, in a study of 80 patients on various IVIg products, the vast majority had false-positive hepatitis B core antibody tests and galactomannan enzyme immunoassays results (2). In this case, misdiagnosis was averted by astute providers considering the patient’s clinical context and negative result prior to pregnancy. However, this case and previous studies imply an important clinical need for identifying patients on IVIg receiving serological testing, perhaps through clinical decision support tools.

Author Contributions

The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list.

Authors’ Disclosures or Potential Conflicts of Interest

Upon manuscript submission, all authors completed the author disclosure form.

Research Funding

None declared.

Disclosures

C.W. Farnsworth received support from CDC BAA 75D301-20-R-68024, CDC BAA 75D301-22-R-72097, Abbott Diagnostics, Cepheid, Qiagen, Sebia, Roche, Siemens, Beckman Coulter, Biomerieux, and Binding Site. He received consulting fees from Cytovale, Werfen, Abbott, Bio-Rad, and Siemens and honoraria from Abbott.

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