Clinica Chimica Acta 447 (2015) 32–33

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Letter to the Editor IgM interference in the Abbott iVanco immunoassay: A case report Keywords: Vancomycin Interference IgM paraprotein Immunoassay

Vancomycin, a potent glycopeptide antibiotic, is routinely monitored in patient's serum or plasma to ensure therapeutic and to avoid toxic concentrations. Enzyme immunoassays are currently the preferred method to measure vancomycin concentrations as they are fast and also widely available. In our setting, vancomycin is routinely measured on the Architect i2000SR analyzer (Abbott Diagnostics) on a serum or plasma sample using a competitive chemiluminescent microparticle immunoassay (iVanco assay, Abbott Diagnostics). Here, we describe a case of IgM interference in the iVanco immunoassay, and a strategy to circumvent the reporting of spurious vancomycin results. An 82-year-old male patient, diagnosed with Waldenström's disease one year ago, was admitted to the Ghent University Hospital with symptoms of anorexia, asthenia, and hyperviscosity syndrome. The patient had a leukocyte count of 55.1 · 103/μL, a monoclonal IgM component of 74 g/L and a total protein concentration of 98 g/L. Hemocultures showed an MRSA sepsis without clear focus. Consequently, this patient was empirically treated with vancomycin (20 mg/kg, followed by a continuous infusion of 25 mg/kg). On the first day of vancomycin therapy, a blood sample was drawn and sent to the laboratory for analysis. The measured vancomycin concentration was extremely high (N100 mg/L), and required further dilution. Surprisingly, measurements on 1/4 and 1/5 diluted serum suggested a lower initial concentration (21.8 mg/L and 17.2 mg/L, respectively). Analysis in an alternative matrix, K2-EDTA plasma, drawn at the same time point, confirmed the result obtained in undiluted serum (N100 mg/L). Analysis of a serum sample, drawn before the start of vancomycin treatment, resulted in a total vancomycin concentration of 70.3 mg/L, which further confirmed the suspicion of an interfering component. Interference due to rheumatoid factor could be excluded (b10.8 IU/mL). Although not included in the product leaflet of the iVanco assay [1], in this sample interference of monoclonal IgM was suspected, given its high concentration. Falsely low vancomycin results due to IgM interference have already been reported for other immunoassays (PETINIA, Siemens, Beckman Coulter) [2,3]. However, to our knowledge, this would be the first report that is describing a falsely high concentration on the Architect i2000SR analyzer. In an attempt to eliminate this interference, the unbound vancomycin concentration was measured after ultrafiltration of the

http://dx.doi.org/10.1016/j.cca.2015.05.006 0009-8981/© 2015 Elsevier B.V. All rights reserved.

patient's serum, as described by Stove et al. [4]. This resulted in an unbound vancomycin concentration of 14.8 mg/L and, based on the previously reported equation Unbound vanco conc = 0.697 ∗ total vanco conc + 0.84 [4], an estimated total vancomycin concentration of 20.0 mg/L, which is within the therapeutic range (reference interval 15–25 mg/L). Subsequent blood samples were measured using the same methodology and gave similar therapeutic results (Table 1). These estimated total vancomycin concentrations were confirmed by re-analysis of the native sera using a validated LC-MSMS method [5] and the Roche VANC2 assay (Cobas c502, Roche Diagnostics), a homogeneous enzyme immunoassay that was not affected by IgM interference in previous reports [2,3]. A dilution series from a sample on day 3 of therapy showed that results are only in a linear relation after ultracentrifugation of the samples (Supplementary Fig. 1). Leftovers of samples from two other patients with a high IgM paraprotein (75.5 g/L and 18.2 g/L, respectively) but not receiving vancomycin therapy, were analyzed for IgM interference in the vancomycin assay. However, in these two cases, vancomycin was below the detection limit, indicating that even in this selected population, interference is not common. As IgM interference in phenytoïn assays has also been described, a sample (on day 3) was tested, but result was b 0.5 mg/L [6]. We conclude that laboratory staff needs to be aware of possible interference of a paraprotein in a vancomycin immunoassay. In contrast with the published falsely low results, we found with our assay spuriously high results. Re-analysis of the specimen by use of protein-free ultrafiltration may eliminate the interference. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.cca.2015.05.006.

Conflicts of interest No authors declared any potential conflicts of interest.

Table 1 Vancomycin concentration of subsequent blood samples on different analytical platforms. Day Total vancomycin (mg/L) LC-MSMS Cobas c502 0* 1 2 3

0.3 19.5 26.3 28.2

b1.7 18.6 24.6 27.2

Architect i2000SR 70.3 N100 N100 N100

Unbound vancomycin (mg/L)**

Estimated total vancomycin (mg/L)***

IgM (g/L)

b1.7 14.8 18.5 19.0

ND 20.0 25.3 26.1

76.7 78.6 73.9 75.9

ND: not determined; *: before vancomycin administration; **: measured on Architect i2000SR;***: Formula: total vancomycin conc = (unbound vancomycin conc − 0.84)/ 0.697.

Letter to the Editor

References [1] Abbott Architect iVancomycin G3, package insert 2012 (Nov). [2] LeGatt DF, Blakney GB, Higgins TN, et al. The effect of paraproteins and rheumatoid factor on four commercial immunoassays for vancomycin: implications for laboratorians and other health care professionals. Ther Drug Monit 2012;34:306–11. [3] Simons SA, Molinelli AR, Sobhani K, Rainey PM, Hoofnagle AN. Two cases with unusual vancomycin measurements. Clin Chem 2009;55:578–80. [4] Stove V, Coene L, Carlier M, De Waele JJ, Fiers T, Verstraete AG. Measuring unbound versus total vancomycin concentrations in serum and plasma: methodological issues and relevance. Ther Drug Monit 2015;37:180–7. [5] Oyaert M, Peersman N, Kieffer D, et al. Novel LC-MS/MS method for plasma vancomycin: comparison with immunoassays and clinical impact. Clin Chim Acta 2015;441: 63–70. [6] Brauchli YB, Scholer A, Schwietert M, Krahenbuhl S. Undetectable phenytoin serum levels by an automated particle-enhanced turbidimetric inhibition immunoassay in a patient with monoclonal IgM lambda. Clin Chim Acta 2008;389:174–6.

Lisa Florin Department of Laboratory Medicine, Ghent University Hospital, De Pintelaan 185 (2P8), Gent, Belgium Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, De Pintelaan 185 (2P8), Gent, Belgium Anna Vantilborgh Department of Hematology, Ghent University Hospital, De Pintelaan 185 (9K12), Gent, Belgium

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Steven Pauwels Department of Laboratory Medicine, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium Timothy Vanwynsberghe Department of Laboratory Medicine, AZ Sint-Jan Brugge, Ruddershove 10, 8000 Brugge, Belgium Pieter Vermeersch Department of Laboratory Medicine, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium Veronique Stove⁎ Department of Laboratory Medicine, Ghent University Hospital, De Pintelaan 185 (2P8), Gent, Belgium Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, De Pintelaan 185 (2P8), Gent, Belgium Corresponding author at: Veronique Stove, De Pintelaan 185 (2P8), 9000 Gent, Belgium. Tel.: +32 93325871; fax: +32 3324985. E-mail address: [email protected] 8 May 2015 Available online 14 May 2015

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