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Additive-aggravated assays: an authoritative answer.

Immunoassay interferences are diverse in scope (1-8) and are the subject of several recent large-scale studies (9,10), opinions, and editorials (6,11). Most interferences originate from components of the sample (e.g., human antianimal antibodies, lipid, bilimbin, drug metabolites) that interact with assay reagents or the detection system.

The latest interference to rear its ugly head has been an interference originating from an additive in a blood collection tube (12-14). In this issue of Clinical Chemistry, Remaley et al. (13) have extended their original work (12) on this problem and have now identified a common tube surfactant as the probable interferent. They show that Silwet[TM] L-720, an organosilane surfactant additive to Becton Dickinson Vacutainer[R] SST[TM] blood collection tubes, causes interferences by desorbing capture antibodies from the solid phase used in the Immulite total triiodothyronine immunoassay. This desorption effect was supported by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by immunoblotting analysis of Silwet[TM] L-720 eluates of the solid-phase antibody used in the Immulite assays.

Now that the source of this interference has been identified, a pertinent question is this: "How can this type of interference be detected in the future?"

Clearly, now that blood collection tube additives have been identified as a possible source of interference in immunoassays, manufacturers of blood collection tubes and immunoassay tests should implement additional quality-control measures. In addition, various control measures may be prudent in the clinical laboratory. One action could be increased vigilance of the running means of patients' results, to detect an unexpected shift. However, this may be of limited or no use for endocrine assays because the range of patient values can be very large in the population tested (e.g., follicle-stimulating hormone concentrations in pre- and postmenopausal women vary over 10-fold and 100-fold ranges, respectively). Hence, there is a large spread of values that would obscure shifts in assay values caused by interference. Another action might be to adhere strictly to the basic tenet of quality control, namely, that the control sample should be treated in exactly the same manner as a specimen from a patient. In most, if not all, clinical laboratories, quality-control samples are poured from the bottle into an assay tube and then placed on the analyzer for analysis. Unlike the specimen from the patient, they do not encounter the contents of a blood collection tube. It would thus seem expedient to analyze samples of quality-control serum that have been poured into a blood collection tube and then processed along with patients' specimens. Comparison of results for control sera that have and have not been exposed to blood collection tubes should reveal adverse effects resulting from additives in the tubes. This strategy would provide a means to detect future interferences resulting from changes in the formulation of additives in blood collection tubes. However, the diverse production lots of blood collection tubes used in various in- and outpatient locations also obscure lot-dependent interferences. It seems more feasible to have manufacturers expose quality-control sera to blood collection tubes on a lot-by-lot basis.

In the meantime, we need to remain vigilant for other immunoassay interferences. Nutritional supplements such as herbal medicines are widely used in the United States (15) and are a potential source of interfering substances that have not been thoroughly investigated. Indeed, assay interferences attributed to traditional Chinese medicines have already been reported in digoxin immunoassays (16-19). An additive-attributable assay aberration is not the first interference to be reported in immunoassays, and it certainly will not be the last.


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(2.) Walker PL, Cawood ML, Barth JH. Interference in immunoassay is an underestimated problem. Ann Clin Biochem 2002;39:366-73.

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(9.) Preissner CM, Dodge LA, O'Kane DJ, Singh RJ, Grebe SK. Prevalence of heterophilic antibody interference in eight automated tumor marker immunoassays. Clin Chem 2005;51:208-10.

(10.) Marks V. False-positive immunoassay results: a multicenter survey of erroneous immunoassay results from assays of 74 analytes in 10 donors from 66 laboratories in seven countries. Clin Chem 2002;48:2008-16.

(11.) Ismail AAA. A radical approach is needed to eliminate interference from endogenous antibodies in immunoassays. Clin Chem 2005;51:25-6.

(12.) Bowen RA, Chan Y, Cohen J, Rehak NN, Hortin GL, Csako G, et al. Effect of blood collection tubes on total triiodothyronine and other laboratory assays. Clin Chem 2005;51:424-33.

(13.) Bowen RAR, Chan Y, Ruddel ME, Hortin GL, Csako G, Demosky SJ Jr, et al. Immunoassay interference by a commonly used blood collection tube additive, the organosilicone surfactant Silwet L-720. Clin Chem 2005;51: 1874-82.

(14.) Becton-Dickinson[TM]. Technical bulletins VS7313 and VS7340. http:// (accessed July 2005).

(15.) Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002;287:337-44.

(16.) Chow L, Johnson M, Wells A, Dasgupta A. Effect of the traditional Chinese medicines Chan Su, Lu-Shen-Wan, Dan Shen, and Asian ginseng on serum digoxin measurement by Tina-quant (Roche) and Synchron LX system (Beckman) digoxin immunoassays. J Clin Lab Anal 2003;17:22-7.

(17.) Datta P, Dasgupta A. Effect of Chinese medicines Chan Su and Danshen on EMIT 2000 and Randox digoxin immunoassays: wide variation in digoxin-like immunoreactivity and magnitude of interference in digoxin measurement by different brands of the same product. Ther Drug Monit 2002;24:637-44.

(18.) Dasgupta A, Actor JK, Olsen M, Wells A, Datta P. In vivo digoxin-like immunoreactivity in mice and interference of Chinese medicine Danshen in serum digoxin measurement: elimination of interference by using a chemiluminescent assay. Clin Chim Acta 2002;317:231-4.

(19.) Wahed A, Dasgupta A. Positive and negative in vitro interference of Chinese medicine dan shen in serum digoxin measurement. Elimination of interference by monitoring free digoxin concentration. Am J Clin Pathol 2001;116:403-8.

Larry J. Kricka*

Jason Y. Park

Department of Pathology & Laboratory Medicine

University of Pennsylvania Medical Center

Philadelphia, PA

* Address correspondence to this author at: Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104-4283.

DOI: 10.1373/clinchem.2005.057885
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Title Annotation:Editorials
Author:Kricka, Larry J.; Park, Jason Y.
Publication:Clinical Chemistry
Date:Oct 1, 2005
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