Plebani

Clin Chem Lab Med 2020; 58(8): 1169–1170
Editorial
Claudio Galli and Mario Plebani
Quality controls for serology: an unfinished

agenda
https://doi.org/10.1515/cclm-2020-0304 for the detection of antibodies directed to the hepatitis C
virus (HCV). The evidences brought up by those authors
The quality control process (QC), both as internal quality are of actual relevance in two different levels, one pertain-
control (IQC) and external quality assessment programs, ing to the analytical environment and the other on the
is a must for clinical laboratories to guarantee consist- clinical side. The analytical issues are described keenly: a
ency and accuracy of results. While QC procedures are change in the reagent lot of the Abbott ARCHITECT assay
well established for clinical chemistry and most immu- for anti-HCV resulted in a downward shift of the low-level
nochemistry analyses that provide a quantitative meas- QC sample employed. The basic questions they tried to
urement, assays employed for the serological testing of answer concern the amount of QC reactivity change and
infectious diseases pose several challenges. First, in this on this purpose, they have compared affected and unaf-
field, a true quantitation is hard to achieve. Most assays fected reagent lots’ reactivity of EQA scheme samples. A
are qualitative and results are expressed as positive or lower reactivity by the affected lots was found on almost
negative by comparing the signal generated to a threshold all samples, and by one affected lot the result was below
value, alternatively called “cutoff”. Secondly, whenever a the reactivity threshold on four specimens.
quantitative result is provided – usually for antibodies – a The second question, and possibly the most relevant
true quantitation is disputable. Even in case a reference one, is how much change is allowed before there is an
standard and International Units (IU) are available for increased probability of reporting an incorrect clinical
reporting results, assays may differ in composition – use result. This has been addressed by analyzing the effect of
of different antigens or of similar antigens with different this change of reactivity on early seroconversion samples
expression – in assay kinetics and in signal generation. on two different sets. Results not lower than the cutoff
A classic example comes from IgG antibodies to Rubella value have been recorded on four samples in the first
virus: most assays are calibrated by (or against?) the WHO set, and in none on the second set, though several speci-
reference standard and the “protective” threshold is set at mens gave results lower than 2.0 times the cutoff on both
10 IU/mL [1], but the absolute values may differ by 10-fold affected and unaffected lots. According to the CLSI EP23A
or more among different assays [2]. guideline, risk assessment depends on a two-factor model
Finally, antibody assays are detecting the relative that includes the probability of occurrence of harm and
affinity to specific antigenic epitopes and thus the signal the severity of harm [6].
generated is deeply influenced by the stage of infection: In this perspective, Dimech et al. correctly indicate
a lower signal may be generated in the late stages or in that the occurrence of a false-negative result for anti-HCV
chronic infections that are under control by the immune in a diagnostic setting is unlikely, as there is a very low
system, with only a few active clones releasing antibod- chance of obtaining a sample during the time span when
ies with high affinity, as well as in acute/recent infections the sample to cutoff value is between 1.0 and 2.0. It shall
when circulating antibodies have a low affinity, though also be mentioned that the current standard for the labora-
the absolute number of activated clones may be higher. tory diagnosis of acute HCV is an HCV antibody serocon-
Despite these limitations, QC schemes for serology version (negative HCV antibody test before a suspected
are in place and the results are evaluated according to exposure and a positive antibody test following potential
the same rules that apply to other immunometric assays exposure), combined with a positive HCV RNA test and ele-
[3], with a few differences [4]. In the current issue of the vated alanine aminotransferase (ALT). In blood donation
Journal, Dimech et al. [5] bring up a substantial contri- screening setting the false negativity may bear a higher
bution to this field by highlighting the relevance of an risk, which is mitigated by the additional pre-donation pro-
eventual shift in EQC values linked to reagent lot changes, cedures and the addition of nucleic acid testing. This paper
reporting how such a change did affect a widespread assay emphasizes the need to move toward a better harmonization
1170 Galli and Plebani: Quality controls for serology: an unfinished agenda
of procedures and processes adopted by clinical laborato- uantification of Rubella IgG antibody, NCCLS Document 12.
q
ries working in different fields of laboratory medicine [7, Wayne, PA: National Committee for Clinical Laboratory Standards,
1992.
8]. It is time to review procedures and processes adopted
2. Valoup-Fellous C. Standardization of rubella immunoassays.
for QC not only in clinical chemistry but in all other fields J Clin Virol 2018;102;34–8.
of laboratory medicine, including microbiology and point- 3. CLSI C24A3. Statistical quality control for quantitative measure-
of-care testing (POCT). The consolidation of different spe- ment procedures. Wayne, PA: Clinical and Laboratory Standards
cialties and analytical techniques in clinical laboratories Institute, 2006.
4. Dimech W, Karakaltsas M, Vincini GA. Comparison of four meth-
answers physicians’ and patients’ need to receive a unique
ods of establishing control limits for monitoring quality controls
and harmonized laboratory report with results from clinical in infectious disease serology testing. Clin Chem Lab Med
chemistry, hematology, coagulation, molecular diagnos- 2018;56:1970–8.
tics and microbiological-virological tests [9]. Technological 5. Dimech WJ, Vincini GA, Cabuang LM, Wieringa M. Does a change
improvements based on common analytical platforms and in quality control results influence the sensitivity of an anti-HCV
advanced informatics tools facilitate this process, but more test? Clin Chem Lab Med 2020;58:1372–80.
6. Westgard JO. Perspectives on quality control, risk manage-
efforts are requested to laboratory professionals as appro-
ment, and analytical quality management. Clin Lab Med
priate and accurate rules for QC are needed to ensure reli- 2013;33:1–14.
ability and accuracy to laboratory information. 7. Lippi G, Plebani M. A modern and pragmatic definition of Labora-
tory Medicine. Clin Chem Lab Med 2020;58:1171.
Author contributions: All the authors have accepted 8. Plebani M. Harmonization in laboratory medicine: more than
clinical chemistry? Clin Chem Lab Med 2018;56:1579–86.
responsibility for the entire content of this submitted
9. Plebani M, Laposata M, Lippi G. Driving the route of labora-
manuscript and approved submission. tory medicine: a manifesto for the future. Intern Emerg Med
Research funding: None declared. 2019;14:337–40.
Employment or leadership: None declared.
Honorarium: None declared.
Corresponding author: Mario Plebani, Department of Laboratory

Medicine, University-Hospital of Padova, Via Giustiniani 2, Padova
References 35128, Italy, Phone: +39 0498212792, Fax: +39 049663240,
E-mail: mario.plebani@unipd.it. https://orcid.org/0000-0002-
1. Skendzel LP, Carski T, Herrmann K, Kiefer DJ, Namamura R, 0270-1711
Nutter C, et al. Evaluation of performance criteria for multiple Claudio Galli: Medical and Scientific Affairs, Abbott Diagnostics,
component test products intended for the detection and Rome, Italy

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Clin Chem Lab Med 2020; 58(8): 1169–1170

Claudio Galli and Mario Plebani

Quality controls for serology: an unfinished

Corresponding author: Mario Plebani, Department of Laboratory

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