Clin Chem Lab Med 2019; aop

Opinion Paper

Martina Zaninotto and Mario Plebani*

Understanding and managing interferences in

clinical laboratory assays: the role of laboratory
professionals
https://doi.org/10.1515/cclm-2019-0898
Received August 23, 2019; accepted September 15, 2019
Introduction
Abstract: The recently raised concerns regarding biotin Several recently published papers underline the rel-
interference in immunoassays have increased the aware- evance of biotin as an “emerging” interferent in immu-
ness of laboratory professionals and clinicians of the noassays [1–3]. Manufacturers, regulatory agencies and
evidence that the analytical phase is still vulnerable to laboratory professionals are striving to find concrete
errors, particularly as analytical interferences may lead solutions to overcome this challenging issue, although it
to erroneous results and risks for patient safety. The issue will take time and money to find a solution and a clinical
of interference in laboratory testing, which is not new, validation, to overcome this problem. However, interfer-
continues to be a challenge deserving the concern and ences in laboratory medicine constitute a more general
interest of laboratory professionals and clinicians. Ana- problem, widely discussed by laboratory profession-
lytical interferences should be subdivided into two types als keen to adopt procedures and algorithms to prevent
on the basis of the possibility of their detection before “clinical episodes” due to inconsistent/spurious results,
the analytical process. The first (type 1) is represented by to suspect “analytical” causes of inconsistent/spurious
lipemia, hemolysis and icterus, and the second (type 2), results and to properly interact with clinical teams to
by unusual constituents that are not undetectable before avoid patient harm.
analysis, and may affect the matrix of serum/plasma Available evidence on the overall laboratory error
of individual subjects. Type 2 cannot be identified with rate (0.012%–0.6%) [4–6] indicates that a minor contri-
current techniques when performing the pre-analytical bution is ascribable to analytical errors (0.078%) [7–9]
phase. Therefore, in addition to a more careful evaluation and, in particular, to interferences in the measurement
and validation of the method to be used in clinical prac- methods, but the real frequency and severity of inter-
tice, the awareness of laboratory professionals should ferences represents a “moving target” related to assays
be raised as to the importance of evaluating the quality conformation, as well as changes in laboratory organi-
of biological samples before analysis and to adopt algo- zation, innovative therapies for some diseases, and in
rithms and approaches in the attempt to reduce problems the lifestyle of the population [10, 11]. Therefore, several
related to erroneous results due to specific or non-specific tasks should be performed by laboratory professionals
interferences. for interferences to be suspected and further investi-
gated in specific circumstances, also when suggested
Keywords: analytical interferences; biotin; immunoas-
by clinicians if the result provided for a specific patient
says; patient safety; quality; quality assurance.
fails to fit with the clinical picture.

Frequency and type of interferences

*Corresponding author: Prof. Mario Plebani, Department of Table 1 shows the main causes of interference in current
Laboratory Medicine, University-Hospital of Padova, Padova, Italy,
laboratory testing. The reported interferences should be
Phone: 0498212792, E-mail: [email protected].
https://orcid.org/0000-0002-0270-1711
subdivided into two types on the basis of the possibil-
Martina Zaninotto: Department of Laboratory Medicine, University- ity of their detection before the analytical process. The
Hospital of Padova, Padova, Italy first (type 1), easy to detect, is represented by lipemia,

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2      Zaninotto and Plebani: Interferences in clinical laboratory assays

Table 1: Main causes of interference in laboratory tests. levels: in fact some laboratories report the results along
with an accompanying comment and others consider
– Lipids, hemoglobin and other serum constituents a “hold index” above which the results should not be
– Anti-reagent antibodies (heterophilic Ab, HAMA, rheumatoid
reported [21, 22]. Finally, it appears of value to use the
factor, biotin)
– Anti-analyte Ab (e.g. anti-thyroglobulin, anti-insulin) HIL indices as an additional diagnostic tool as demon-
– Macrocomplexes (macroprolactin, macro-TSH, macroenzymes) strated by some authors [23, 24]. Therefore, even if the
– Paraproteins harmonization process may improve the management
of some pre-analytical interferences, the state-of-the-art
emphasizes the need for both adequate and accurate
hemolysis and icterus, and the second (type 2), by professional knowledge and valuable technical support
unusual constituents that are not undetectable before for monitoring potential errors arising from these spe-
analysis, and may affect the matrix of serum/plasma of cific problems.
individual subjects. Yet type 2 cannot be identified with
current techniques when performing the pre-analytical
phase.
Analytical interferences

Pre- and post-analytical interferences Although rare, type 2 interferences are responsible for
inaccurate, sometimes grossly incorrect, test results,
The process of laboratory testing has three recognized some of which are known to translate into a potential
phases, the pre-and post-analytical phases being well cause of patient harm [25]. The frequency rate of these
understood and acknowledged at an international level interferences is difficult to ascertain because no studies
[12, 13]. Recent decades have seen a greater awareness of in the literature have been specifically designed to eval-
the interplay and interconnection between the pre- and uate whether false-positive or false-negative results due
post-analytical phase with the inter-analytical process to this type of analytical interference have been pro-
[6]. In fact, in the pre-analytical phase, type 1 interfer- gressively modified over time [26]. In addition, as the
ences influencing the accuracy of results (such as hemol- frequency of these interferences may change according
ysis, icterus, lipemia) have been rigorously addressed, to the type of clinical workload (e.g. the ratio between
with a well-developed quality indicator system that inpatients and outpatients), changes in dietary habits
allows in reliable monitoring of their rate [14, 15]. The and medical treatments, the phenomenon should be
manufacturers of modern biochemistry analyzers have considered widespread. In fact, interferences may affect
developed instruments able to objectively quantify particular measurement techniques [27] and in par-
hemoglobin, bilirubin and turbidity (HIL indices) in ticular immunoassays (heterophilic antibodies, HAMA,
serum or plasma samples by adopting multiple spec- paraproteins, immunocomplexes, rheumatoid factors,
trophotometric measurements, and are therefore able etc.) [28, 29], whole analysis platforms (e.g. assays based
to identify HIL interference much more accurately than on biotin-streptavidin principles) [1], and/or single spec-
with the traditional visual approach [16–18]. On the imens in spectrophotometric methods (such as macroen-
other hand, professional laboratories using biochem- zymes) [30, 31].
istry analyzers from multiple manufacturers, as well A reported test result that is grossly “abnormal”, is not
as laboratory networks in which a variety of analytical comparable with previous results from the same patient,
platforms are used, face an additional layer of complex- or does not fit with the clinical picture may immediately
ity when they attempt to harmonize their handling of raise the suspicion of inconsistent results ascribable to
HIL interference [19]. In such scenarios, consideration interferences. In other cases, a suspected interference
first needs to be given to how HIL index results from the may be confirmed only after several instrumental and
different platforms compare and, second, to how HIL laboratory investigations have been performed to rule
interference affects results from an individual analyzer. out the possible diseases and conditions responsible
Some papers report, for example, satisfactory agreement for those abnormal results [32]. Consequently, time and
between the hemolytic index calculated from different resources should be invested for a definitive comprehen-
platforms and the reference method [16, 20]. Instead, sion and classification of the analytical problem thus
a lack of harmonization is recognized when reporting incurring possible delays in results reporting and patient
the results in samples with HIL indices above the alert discomfort.

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 Zaninotto and Plebani: Interferences in clinical laboratory assays      3

The methodological approach the first line approach should be an exact understanding
of the robustness of the system and the assay adopted,
Various technical algorithms and methods have been as well as inherent limitations associated with it, profes-
suggested in order to start the investigation procedure if sional reasoning supported by specific algorithms and
an erroneous result from interference is suspected [33]. objective criteria are of utmost importance in evaluating
Although internal quality assessment (IQA) and external results [38]. In particular, an unusual result probably due
quality assessment (EQA) control programs are funda- to interferences, may be suspected if one or more of the
mental tools for monitoring the quality performances of issues listed in Table 2 are observed.
laboratory methods, they are only able to evaluate the In addition, recent papers [34] suggest an algorithm
“overall” analytical process, but do not enable the detec- based on the Bayesian approach, which could include
tion of ­erroneous results in an individual sample [34]. several specific quality indicators (e.g. prevalence/inci-
The adequate understanding of the limitations, and of dence of some specific clinical conditions, demographic
the specific analytic characteristics and performances of parameters, interrelationship between immunoas-
the method used, may thus facilitate the starting investi- say results and some laboratory and functional tests).
gation: first of all from the professional point-of-view, an However, this and other described models should be con-
“irregular” result should be confirmed by repeating the sidered only as a starting point, no final decision being
assay on the same specimen, or on the original sample made as to whether or not an analytical result should be
if an aliquoting procedure has been carried out, in order accepted and reported. Accordingly, further strategies
to rule out the possibility of an analytical/pre-analytical are needed to demonstrate or exclude that an individual
error. Furthermore, in most cases it is advisable for the sample value is actually a false-positive or false-negative
investigating laboratory to send an aliquot of the specimen result. Some authors [33] have suggested that a reliable
to other laboratories to confirm the result by one or more flow chart showing the sequence of laboratory tests can
different methods, ideally an alternative methodology. If, be performed to investigate individual samples with sus-
after taking into account the method-related differences pected interferences, others [38] have discussed in detail
in the bias as reflected in EQA and other available data, the most commonly used investigations, which are inex-
the results differ significantly, this provides convincing pensive, pragmatic and quick to perform and therefore
evidence of the interference although the “correct” result relevant for all clinical laboratories. Prompted by these
will not necessarily be identified [35]. However, these basic suggestions, in daily routine practice we have adopted
investigations may confirm the presence of interference a “standard algorithm”, which is simpler than that pro-
and, from this starting point, different and sometimes posed elsewhere [33–38]: based on a clinical or laboratory
more complex studies should be carried out depending on professional suspicion, it allows us to search for the more
the measure and platform or assay involved [33, 36]. The frequent interferences.
algorithm adopted and the type of investigation mainly For some well-known interferences, such as macro-
used in routine daily practice are reported in Figure 1. prolactin [39], in samples showing concentrations higher
than 30 μg/L at the first observation, we implemented an
automatic rule on the laboratory information system (LIS)
Professional reasoning that produces a second level test, allowing the monomeric
form to be determined, after PEG 6000 precipitation. The
Several approaches have been recommended in the concentration of the monomeric form obtained, in asso-
attempt to reduce problems related to erroneous results ciation with the specific reference interval and the per-
due to specific or non-specific interferences that are centage with respect to total prolactin, is reported with
­undetected by routine laboratory quality control proce- an additional interpretative comment. In our experience,
dures and reproducible within the test system; these errors analogous types of interference (immune/macrocomplex)
are relatively rare, but sometimes clinically plausible, and have been observed in troponin I assays (in some cases
any individual analytical error may seriously compromise irrespective of the method, particularly in patients present-
patient care [37]. Furthermore, as shown by daily experi- ing the IgG-TnI immunocomplex), as well as in vitamin B12
ence of test results, any type of assay or test may be sus- and calcitonin assays. In addition, several cases of immu-
ceptible to analytical interference as “a perfect assay” is nocomplex involving different enzymes (alfa-amylase,
non-existent. Consequently, greater concern should be creatinphosphokinase, lactate dehydrogenase, aspartate
paid by laboratory professionals to the validation/moni- aminotransferase) have been correctly identified by adopt-
toring procedures on obtained analytical results. Even if ing the standard algorithm described in Figure 1.

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4      Zaninotto and Plebani: Interferences in clinical laboratory assays

Suspicious based on: – Plausibility

– Delta check
– Clinician claim

– Check specimen identity

– Confirm the result on the same specimen

If confirmed, repeat the measurement

with an alternative method (eventually
sending the sample to other laboratories)

Original result unequivocally confirmed

with the original assay but not with the
alternative technique

Alert clinicians and undertake further investigations

according to the measurement method

Spectrophotometric and/or Immunoassays: Immunoassays

Immunonephelo/ based on
immunoturbidimetric: – Dilution; Streptavidin/biotin:
– PEG 6000 treatment;
– Dilution;
– Immunoprecipitation; – Dilution;
– PEG 6000 treatment
– Heterophilic blocking T; – PEG 6000 treatment;
– Immunoprecipitation;
– Analyte extraction by – Immunoprecipitation;
– Immunosubtraction.
organic solvent. – Heterophilic blocking
T;
– Analyte extraction by
organic solvent;
– Biotin removal
procedure.

Figure 1: Flow-chart and main types of investigation suggested for assessing suspected interferences.

Table 2: Characteristics of “suspicious analytical results” due to

interferences.
Appropriate interaction with clinical
teams and patients
– Inconsistent with results of other biochemical parameters
– Unusual in more than one assay (in particular The last step is continuous, effective communication and
immunoassay) exchange of information between clinicians and labo-
– Significantly and inexplicably changed in comparison to
ratorians in order to minimize the risk of clinical errors
previous results (delta-check, transversal and longitudinal data
assessment, plausibility checks)
arising from erroneous analytical results [33]. This can be
– Grossly and permanently “abnormal” (in an apparently health achieved mainly by informing clinicians when immuno-
subject) assay results may be particularly vulnerable to interfer-
– Clinically unexpected (after the communication with ence, and always encouraging them to question results
physician) that, on the basis of the clinical picture, are unexpected
– Inconsistent with other clinical correlates
[40].

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 Zaninotto and Plebani: Interferences in clinical laboratory assays      5

Good samples make good assays

Interference
detection
(eg serum
index)

Good post-analytical quality makes

good laboratory information

Check
for
possible
interference

M. Plebani
Figure 2: The “five rights paradigm” integrated by managing the interferences in pre- and post-analytical phases (from [6], modified).

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6      Zaninotto and Plebani: Interferences in clinical laboratory assays

Furthermore, patients for whom there is evidence the concern and interest of laboratory professionals
of endogenous assay interference should be informed and clinicians and, even some technologies appear less
that they are at risk of future false-positive results, and vulnerable (e.g. mass-spectrometry assays), cannot be
should be encouraged to report this risk whenever they fixed only by technological approaches. In addition to
have a blood specimen taken. This information should a more careful evaluation and validation of the method
also be contained in the patient’s personal medical record to be used in clinical practice, the awareness of labora-
(HER), as well as in a letter to the family doctor, in par- tory professionals should be raised as to the importance
ticular when the wrong result might be attributed to an of evaluating the quality of biological samples before
­endogenous component that might give rise to the same analysis; they should be encouraged to mainly adopt
interference in other tests. HIL indices to identify type 1 interferences in the pre-
analytical phase. After an analytical result has been
obtained, plausibility and delta-check analyses should
Conclusions be used in the post-analytical phase to identify possi-
ble interferences. Finally, in the post-post-analytical
The recently raised concerns regarding biotin interference phase any request by a clinician to verify an analytical
in immunoassays has increased the awareness of labora- result should be carefully considered, and should pave
tory professionals and clinicians of the evidence that the the way to further investigations, as shown in Figure 1.
analytical phase is still vulnerable to errors. Although the The true remedy for the issue of interference in labo-
state-of-the-art highlights the vulnerability of extra-ana- ratory medicine, therefore, starts from improving the
lytical phases, the metric adopted in many studies may appropriateness of test requests and information about
lead to overconfidence in analytical quality. Indeed, each the sample specimen, and may end by discovering and
and every individual sample potentially presents a specific identifying possible rare and obscure causes of implau-
matrix, sometimes due to an altered ratio between differ- sible results.
ent measurands (e.g. in end-stage renal disease patient On the basis of the discussed issues and, as ­highlighted
samples) or to the presence of cross-reactants, anti-reagent in Figure 2, the “five rights” paradigm describing the total
and anti-analyte antibodies. While IQA and EQA p ­ rograms quality process in laboratory medicine [6] should be inte-
evaluate the overall quality of an analytical series, they grated with the management of the interferences that may
cannot adequately allow an evaluation of the risk of errors influence the pre-analytical as well as the post-post ana-
in all patient samples. In some groups of patients and indi- lytical phases.
viduals, even well-standardized reference measurement
procedures and results validated by traditional statistical Author contributions: All the authors have accepted
control procedure, may still be affected by interferences responsibility for the entire content of this submitted
thus generating erroneous results. manuscript and approved submission.
In the case of type 1 interferences, improvement Research funding: None declared.
in pre-analytical phase thanks to the introduction of Employment or leadership: None declared.
workstations able to identify the presence of excessive Honorarium: None declared.
endogenous components, such as hemoglobin, bilirubin Competing interests: The funding organization(s) played
and lipids, is an effective tool for obviating the risk of no role in the study design; in the collection, analysis, and
erroneous results. However, in the case of type 2 inter- interpretation of data; in the writing of the report; or in the
ferences, the presence and nature of the interfering decision to submit the report for publication.
substance cannot be identified and predicted before
analysis. In the case of biotin, the risk of error should be
predicted more easily than in the case of other interfer-
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