Chapter

Challenges with Point-Of-Care

Tests (POCT) for Celiac Disease
Huan Wu, Michael Wallach and Olga Shimoni

Abstract

Current screening test for celiac disease involves blood test in centralized pathol-
ogy laboratories, typically performing enzyme-linked immune-sorbent assays
(ELISA) to detect specific celiac disease antibodies. Most of the current available
celiac disease antibody tests detect anti-gliadin (AGA), anti-endomysial (EMA),
anti-transglutaminase (tTG), or deamidated gluten peptide (DGP) antibodies
from serum or whole blood samples. It requires blood collection from untreated
celiac patients, which is often invasive and inconvenient. There is a rapid growth in
demand for noninvasive celiac tests for the early and fast diagnosis of celiac disease
to help potential celiac patients obtain results and take corresponding actions.
Over the last decade, several point-of-care tests (POCT) have been introduced to
the market, but these tests have not been widely accepted by clinicians. Moreover,
the 2009 NICE guideline CG 86 recommended that self-tests and/or POCT for
celiac disease should not be used as a substitute for laboratory-based tests. Here,
we provide a background on the evolution of POCT for celiac disease. We discuss
general principle of operation for the known commercial kits as well as the use of
various antigens and antibodies in different tests developed over the years. Finally,
we discuss challenges for future research directions in celiac disease POCTs.

Keywords: celiac disease, point-of-care tests, lateral flow test, immunoassays

1. Introduction

Celiac disease is defined as a lifelong condition as a result of ingestion of gluten

among genetically susceptible people that can be relieved by the introduction of
gluten-free diet; the condition relapses with gluten intake [1]. Recent studies show
that it is prevalent around the world, covering from the western world, such as
Europe and America, to Oceania, Africa, and Asia. The number of celiac sufferers
increases, doubling its number every two decades [2]. The symptoms vary at a wide
range, from flatulence, constipation, anorexia, irregular bowel habits, and irritabil-
ity to numbness in limbs, foggy mind, diarrhea, and depression [3]. Therefore, it
is hard to recognize the condition and deliver the diagnosis. In fact, almost 90% of
celiac patients remain undiagnosed, due to the nonspecific or absent symptoms over
a long period [4]. Thereby, it is of paramount significance to achieve the early-stage
diagnosis of celiac disease that can lead to improving the patients’ quality of life.
The current gold standard of celiac disease diagnosis, which has been also devel-
oped in a much earlier period, is to observe the small intestine atrophy obtained
through biopsy [1]. This process is highly invasive, time-consuming, and inconve-
nient to both patients and clinicians.

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Celiac Disease - From the Bench to the Clinic

Over the last several decades, researchers have found that the concentration
of some certain antibodies circulating in celiac patients’ body increased, and the
detection of celiac disease can be achieved with the detection of these antibodies.
In fact, the surface of mucosa represents the major targeted sites when foreign
antigens attack the body [5]. Plausibly, 80% of all cells producing immunoglobulin
(IgG) in the human body are in small bowel mucosa, which also produces the
dimers of IgA [6]. Therefore, the antibodies of celiac disease among untreated
patients are located in the mucosal surface [7], as extracellular deposit, some
present in jejunal juice [8], and most in the intestine [9, 10]. For untreated celiac
patients, the additional generation of antibodies leads to an increase of antibodies
specific to celiac disease (IgA− class), most of which can be found in the circulat-
ing blood and some other bodily fluids. Among all the celiac-specific antibodies,
anti-reticulin (ARA), anti-jejunal (JEA), endomysial (EMA), and tissue transglu-
taminase antibodies (tTG) are among the patients’ own endogenous biomolecules
that form as a result of immune response to antigen in the intestine, whereas
anti-gliadin antibody (AGA) and deamidated gliadin peptide antibody (DGP-Ab)
are formed directly against dietary gliadin [11].
Over the years, the detection of the celiac-related antibodies has shown promis-
ing results, and whole blood- or serum-based pathology tests are regularly used
for screening for celiac disease. Typically, screening for celiac disease includes tests
for identification of titers for AGA and/or anti-tTG antibodies, and most of these
tests are based on enzyme-linked immunoassays (ELISA). Even though the method
of ELISA can reach a high sensitivity and specificity, these tests cannot be used
on their own in the process of celiac disease diagnosis. Furthermore, pathology
tests are typically confined to centralized laboratories, where expert personnel is
required, leading to slow- and high-cost detections. Thereby, it is not suitable for
the use outside hospitals, such as clinical offices or home settings, leaving a high
number of undiagnosed celiac cases, especially when their symptoms are not obvi-
ous or do not affect their normal life. Thus, simple and rapid detection methods are
in high demand to be developed.
Fast, accurate, and noninvasive early diagnosis methods and/or devices are
needed to achieve the detection of celiac disease with high sensitivity and specificity,
especially facing the rapid increasing number of celiac patients. Over the last decade,
several point-of-care blood tests have been developed and applied for celiac diseases
screening. The most prominent tests are Simtomax® Blood Drop system (Augurix SA,
Switzerland) and Biocard™ celiac test (AniBiotech®, Finland), lateral flow immuno-
assays that detect anti-tTG and/or anti-deamidated gliadin peptide antibodies.
Lateral flow test, also called lateral flow immunoassay or test strip, has been
widely and commercially used in the rapid detection of many diseases and condi-
tions, such as HIV, illicit drugs, and early pregnancy [12]. In the following sections,
we will discuss and compare several commercial kits available as POCT devices for
celiac disease. The principle of lateral flow test is outlined in the next section.

2. Lateral flow immunoassays

Lateral flow immunoassay is a simple immunochromatography technology that

has successfully applied for rapid diagnostic testing [12, 13]. It typically made of
nitrocellulose or paper-based porous membrane that makes it ideal to fabricate
low-cost devices with little maintenance requirements. Porous membrane enables
the separation, capture, and recognition of the target analytes. In addition, porous
nature of the material facilitates movement of fluids, such as a whole blood, serum,
or urine, by means of capillary action with no external force required.

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Figure 1.
Schematic representation of lateral flow immunoassay in a capture format. Various important parts of the test
are identified as sample, conjugate, and absorbent pads, nitrocellulose membrane with test and control lines.

There are several types of lateral flow assays available, but the most popular is
the capture format. There are two types of capture: “sandwich” and competitive
capture [13].
Overall, lateral flow immunoassay consists of four parts: sample pad, conjugate
pad, nitrocellulose membrane (test line and control line labeled on it), and absor-
bent pad (also called wicking; Figure 1). Typically, fluid sample (blood, serum,
urine, saliva) is added onto sample pad. Through the capillary action, the liquid
moves to the conjugate pad, where preloaded recognition element (conjugated
nanoparticles or colored reagent) is imbedded. The sample and the recognition
reagent react commonly through antigen-antibody interaction. The sample together
with the recognition element continues flowing within nitrocellulose membrane
toward test and control lines. Depending on the type of a capture, sandwich or
competitive, the test line would show a colorful line or disappear, respectively.
Control line always shows colorful signal to indicate the correct functionality of the
test. Absorbent pad function is to collect all the unreacted reagents as well as excess
of liquids.
Lateral flow immunoassay for celiac disease is typically used to detect antibod-
ies, such as anti-tTG, anti-DGP, and AGA antibodies from the whole blood or serum
in a sandwich type of detection [14–18]. Preloaded reagent can be gold nanopar-
ticles or dye conjugated to antigens, such as transglutaminase, deamidated gliadin
peptides, and gliadin protein fragments. The detection of celiac disease-related
antibodies will present as color test line that can be usually seen by the naked eye.
Lateral flow test or strip test is often used as a point-of-care test (POCT) due
to its high specificity, visual color confirmation, and, especially, because of no
additional instrumentation is required. In fact, most of the current commercial
POCTs for celiac disease are based on lateral flow assay to detect antibodies. In the
following section, we will discuss and make a comparison among commercial kits
available together with the outlining principles of POCT device for celiac disease.

3. Point-of-care tests for celiac disease

3.1 Current commercial point-of-care tests

One of the most widely used commercial kits for celiac disease detection is
the new generation of Biocard™ celiac test (AniBiotech®, Vantaa, Finland). In
this commercial kit, lateral flow method was utilized to detect human anti-tTG
IgA antibodies from a whole blood. Gold-labeled anti-human IgA antibodies are

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Celiac Disease - From the Bench to the Clinic

prefixed on the conjugate pad, protein that binds to tTG antigen on the test line and
anti-mouse IgG antibody on the control line [19].
The procedure is as follows: first, a drop of whole blood is taken from a finger
prick, and then, the assumption is if the blood sample contains anti-tTG antibody,
it will complex with liberated self-tTG found on hemolyzed red blood cells. Then
the complex will flow to the conjugated pad due to the capillary force, forming a
larger complex with anti-human IgA labeled on gold colloids. The larger aggregate
is then recognized and captured by the tTG binding protein on the test line, and the
red color will appear. The excess gold-labeled anti-IgA antibodies migrate further
to control line, combining with anti-mouse IgG antibodies, which is prefixed on the
control line, producing another red line (Figure 2). Both red lines represent positive
result; only one red line in the control line means negative. If neither of the lines
turns red, it means the subject is IgA deficient, or the test did not function properly.
Usually the result can be viewed within 5–10 min; positive result can even appear
after 2 min.
Since the Biocard™ celiac test has been made available on the market, a consid-
erable number of papers have evaluated its sensitivity and specificity. Though the
reported sensitivity and specificity vary in a wide range, most of them are around
90%, where some can reach as high as 93 and 94% for sensitivity and specificity,
respectively [19–24]. However, this result is slightly lower than laboratory-based
celiac disease test (more than 95%); therefore, this commercial kit can be only used
for screening for celiac disease, but not for diagnosis. Nevertheless, this test can be
also used to detect patients who have IgA antibody deficiency.
Another widely available POCT is Simtomax® Blood Drop system (Augurix SA,
Switzerland). It is also a lateral flow assay device but slightly more sophisticated as
it presents with two test line, A and B, in addition to a control line [25]. Test line A
is used to detect both anti-DGP IgA and IgG antibodies, while test line B is for the
detection of the whole IgA antibodies. Control line detects the presence of antibod-
ies by capturing with anti-mouse antibodies. On the test line A, synthetic DGP is
embedded to capture and detect anti-DGP IgA and IgG. For the test line B, mouse
anti-human IgA detects total IgA. For the conjugate pad, it is secondary antibodies
combined with gold colloid. If anti-DGP present in the patient’s serum, anti-DGP
will be captured by the secondary antibodies in the conjugate pad, and then the com-
plex will flow further to the test line A and B, captured by A and B, and line A and B
will become red. For the control line, goat anti-mouse antibodies are pre-attached;

Figure 2.
Scheme of Biocard™ celiac test.

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the excess conjugate of gold colloid with secondary antibodies can interact with it
forming red line. All these three lines can be formed after 10 minutes, but not later
than 15 min. Three red lines mean that the patient is celiac disease positive and has
no IgA deficiency. If only two lines become red, in test line A and control line, then
it represents that the subject is positive for celiac disease and IgA deficient, while
two red lines, line B and control line, indicate that the subject is healthy, negative for
celiac disease, and has IgA deficiency. Only one red line on the control means that
the subject is negative for celiac disease but positive for IgA deficiency. If all of these
three lines do not turn red demonstrating a non-valid result, meaning the patient
needs a further test with a new device.
Various assessments have been done for this commercial kit, and it has been
proved to have high sensitivity (95–100%) and specificity (93.1–95.7%) [26–28].
However, specificity of this test drastically reduced when used for patients on
a gluten-free diet [26, 29]. This is not surprising as the amount of celiac-related
antibodies will decrease with a strict following of gluten-free diet but still can be
present due to unaware consumption of gluten.
Except the above two simple and popular POCT kits, additional lateral flow test
has made commercially available, Stick CD 1 and 2 [30]. Stick CD 1 can detect IgA,
IgG, and IgM antibodies against human tTG, while Stick CD 2 also detects AGA
antibodies. It was demonstrated that the sensitivity of Stick CD 1 was 97% and as to
CD 2, 95% for anti-tTG antibodies and 63% for AGA antibodies. The specificity of
CD1 has been shown to reach 99%; as for CD 2, it was 99% for anti-tTG antibodies
[30].
There are multiple ELISA-based tests that are widely available to identify celiac
disease, such as Celikey® or QUANTA®. Typically, these kits use ELISA assay to
detect IgA anti-tTG and/or anti-DPG antibodies. The reported sensitivity and
specificity have been reported to be higher than 90% [31–33]. QUANTA® products
have a various series of commercial kits and can detect different biomarkers with
high sensitivity and specificity for celiac disease detection [34] (Table 1), includ-
ing IgA anti-DGP, IgG anti-DGP, IgA human anti-tTG, IgA, and anti-tTG/DGP
screening. It can be seen from Table 1 that the performance of traditional ELISA-
based test is still slightly higher than that of any lateral flow tests. This is one of the
reasons that most of the gastroenterologists have not accepted the use of POCT as
an alternative to the lab-based tests.

3.2 Research development for point-of-care tests

Although there are some commercial products for the assay of celiac disease
in the market, the effort has not been stopped to devise a low-cost kit with high
accuracy. In 2005, Korponay-Szabó et al. developed a POCT that could rapidly
detect the autoantibodies of tTG from blood sample [35]. The test is based on a

Test Sensitivity (95% CI) (%) Specificity (95% CI) (%)

IgA DGP 98.4 (91.4–99.7) 92.7 (85.5–97.1)

IgG DGP 95.2 (86.7–99.0) 100.0 (96.2–100.0)

IgA human tTG 95.2 (86.7–99.0) 97.9 (92.8–99.7)

IgA and IgG DGP screen 96.8 (89.0–99.5) 99.0 (94.4–99.8)

tTG/DGP screen 100.0 (94.3–100.0) 92.8 (85.8–97.1)

Table 1.
Performance of QUANTA lite celiac disease tests in a high-risk population.

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Celiac Disease - From the Bench to the Clinic

Nunc-Immunostick (Denmark) principle with a four-wing stick. The two wings of

the stick are pre-covered with gelatine to recognize and capture self-tTG/anti-tTG
antibody complexes from the hemolyzed patient blood sample. The third wing
is fixed with anti-human IgA antibodies, to combine with plasma IgA, which is
used as a positive control. The fourth wing has no coating leading to the absence of
antibody capture, and it serves as a negative control. In the test process, one drop
of blood is inserted into the hemolyzing solution and incubated with the stick for
15 min. Then, the stick is washed with water and immersed for another 15 min in
the solution of peroxidase-labeled anti-human IgA. To obtain a visible signal, the
stick is washed again and then inserted into tetramethyl benzidine solution, which
is used as a color reagent, to observe the color change. If these three wings become
blue within 5 min, it means that the result is positive for celiac disease. Negative
result can be confirmed when only the IgA-sensitive part turns blue. If no blue color
appears, it indicates that the sample was IgA deficient, and the test is invalid. It was
demonstrated that the sensitivity and specificity were 97.0 and 96.9%, respectively,
after testing 164 human blood samples of untreated celiac patients [35].
In recent years, another design for POCT device to detect celiac disease has been
based on electrochemical biosensor. The desirable features of POCT, such as low
cost and ease of operation, match well with the utilization of electrochemical bio-
sensor [36]. It makes biosensors suitable for the commercial applications. Moreover,
commercial device to detect blood glucose has been widely used in clinics and
households, boosting motivation of researchers to devise electrochemical sensors
for the rapid test of celiac disease.
In 2012, Adornetto et al. developed a novel fast immunosensor to achieve
anti-tTG antibody detection based on magneto-electrochemistry from serum
samples [37]. In this system, tTG antigen-coated magnetic beads are used to
capture and detect antibodies against tTG from positive serum samples. Alkaline
phosphatase-labeled anti-human IgA antibodies are used as a control. Magnetized
screen-printed electrodes coupled with a portable instrument serving to read out
electrochemical signal, which is produced after the addition of α-naphthyl phos-
phate that is enzymatically converted into the electrochemically active α-naphthol
product. The device was used to analyze 107 blood serum samples (46 positive vs.
61 negative samples), and it was able to identify with a clinical sensitivity of 100%
and a specificity of 98.36%, while the cutoff was 1.0 AU/ml. This is comparable to
spectrophotometric ELISA kits (98.57%, 100%, and 7.00 AU/ml, respectively).
Interestingly, in 2015, Adornetto et al. have engineered another electrochemi-
cal immunoassay system to detect the IgA anti-tTG antibodies [38]. The authors
described a similar system, but the biggest change was that this device is used for
the detection of celiac disease in saliva sample with high sensitivity. This is the
first report that overcomes the problem associated with saliva samples, such as low
levels of IgA anti-tTG antibodies and high liquid viscosity. In this device, magnetic
beads were covered with the tTG antigen to react with antibodies against IgA anti-
tTG, which would typically be present in saliva samples of positive celiac disease
patients. The marker in this case was the conjugate of anti-human IgA and alkaline
phosphate enzyme. The electrochemical transducer was created with a strip of eight
magnetized screen-printed electrodes. This device showed the clinical sensitivity of
95% and specificity of 96% when analyzed in 66 saliva samples. The results show
the suitability for this POCT as noninvasive screening for celiac disease.
In another study, a modular electrochemical peptide-based sensor was devel-
oped to detect anti-DGP antibody [39]. In this approach, firstly a short helical
support peptide (SP) was immobilized on the surface of a gold electrode, followed
by functionalization of SP with DGP and methylene blue (MB), which are used as
the antigen and electrochemical tag, respectively. When the added anti-DGP IgG

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monoclonal antibody was recognized and then bound with the DGP, the transfer
electrons efficiency between DGP and gold surface was reduced, leading to a
signal decrease in a potentiometer. This unique modular style could guarantee the
background of high currents when DGP antibody is absent, even at low surface
densities of DGP. This means that this system could achieve a low-limit detection
of anti-DGP. Although this system presents a great potential, it was not properly
assessed on a real human serum or saliva sample from celiac patients. Nevertheless,
it represents an alternative direction for the future development of POCT device.
A creative electrochemiluminescence immunosensor for the test of tTG was
designed based on the detection platform of a membrane-templated gold nano-
electrode ensemble [40, 41]. In this platform, tTG antigen was first immobilized on
the surface of polycarbonate to capture the target anti-tTG antibody present in the
sample. Then it could react with the biotinylated secondary antibody, which was
labeled with ruthenium-based electrochemiluminescence reagent modified with
streptavidin. The application of an oxidizing potential could induce the generation
of intense and sharp electrochemiluminescence signal, which was used to analyze
different concentrations of anti-tTG. The result showed that its linear range was
between 1.5 ng/mL and 10 μg/mL, with a detection limit of 0.5 ng/mL. This system
was applied to detect human sera samples from five celiac patients and two healthy
controls as a proof of concept for screening test of celiac disease with great out-
comes. Nevertheless, this test still requires more human samples and more vigorous
validation for the potential in POCT application.
Recently, our group has developed a novel one-step test for screening celiac
disease [41]. The test is based on a precipitation principle of gliadin peptide-coated
gold nanoparticles. In this test, diluted serum is added to the prepared peptide-
coated gold colloids in a small tube. If AGA antibodies are present in serum, it
causes agglutination of gold colloids and essentially leads to a colloid precipitation.
The test was used on 30 human serum samples (26 positive celiac samples and 4
controls) in a blinded assessment. The test demonstrated an overall sensitivity and
specificity of over 85%, indicating that this assay has potential to be adopted as
screening tool for celiac disease. Furthermore, this test could be a part of an exclu-
sion-based diagnostic strategy in testing high risk of celiac disease populations.

4. Outlook for the future POCT development

Over the last decade, several POCTs have been introduced to the market, but
these tests have not been widely accepted by clinicians [42]. Moreover, the 2009
National Institute for Clinical Excellence (NICE) guideline CG 86 recommended
that self-tests and/or POCT for celiac disease should not be used as a substitute for
laboratory-based tests [43]. Therefore, even though the current POCT devices can
be used to detect celiac disease with a relatively high sensitivity, their specificity
somewhat lags behind lab-based tests. However, one of the biggest drawbacks of the
current available POCTs is their lack of usability by a non-trained person.
Most of the lab-based tests for celiac disease are performed by trained clinical
technicians, but POCTs are generally aimed to be performed by a non-trained
person. Multiple steps and components, such as blood drawn from a finger prick,
accurate amount of blood requirement, addition of dilatants or other solutions and
visual interpretation, would typically introduce user errors leading to a decrease in
accuracy of the tests. The usability of POCTs has been assessed on the example of
HIV self-testing kits [44]. In this particular study, authors found that almost 50%
of the untrained participants performing POCT HIV test had made multiple errors
during testing. It is clear that for a successful adaptation of POCTs across the globe,

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ideal self-test kits must include easy-to-understand instructions, preferably one-

step operation and easy-to-interpret results.
As discussed above, most of the POCT systems utilize whole blood or serum
samples for celiac disease detection. Drawing blood from vein or from finger prick
can be viewed by some people as invasive and painful leading to a withdrawal
from voluntary testing. In addition, all the mentioned laboratory or POCTs target
autoantibodies, such as antibody against tTG, DGP, or even EMA. It means that
celiac disease can only be detected after antibodies are circulated in the human
body. However, antibody-based tests generally fail at the latent or silent cases of
celiac disease or people on voluntary gluten-free diet. Can we achieve celiac disease
detection when there is a low amount or no antibodies found? Maybe it is another
challenge that researchers have to face when devising the future screening methods
and tools for celiac disease.
In other fields of analyte detection, including the detection of blood glucose, on-
site alcohol and illicit drug tests, and confirmation of pregnancy, there are already
various well-developed and commercialized products from different brands. These
examples comprise of the use of nanotechnology, microfluidics, or the combination
of these two methods together that provide some inspiration for future methods
of POCT for celiac disease. In particular, highly accurate and sensitive fast test of
HIV [45, 46], tuberculosis [47–49], and malaria [50–52] combine the utilization of
lateral flow microfluidics with visual colorimetric observation detection. Indeed,
these POCT diagnostic devices can probably provide the most effective and useful
tool for mass diagnosis. Additionally, these tests have been proven to be cost-effec-
tive, simple, and portable, as well as with capacity for multiplexing.

5. Conclusion

In conclusion, this chapter has reviewed the current commercially and labora-
tory-based developed POCT devices and the challenges to be faced with for a rapid
and simple test of celiac disease. It is expected that more efforts of multidisciplinary
research involved in immunology, lateral flow technology, microfluidics, nanotech-
nology, and genetics could provide a great opportunity for the fast, accurate, and
early diagnosis of celiac disease, dramatically improving the quality of human life.

Acknowledgements

Dr. Shimoni acknowledges the Australian Research Council, National Health

and Medical Research Council, and AMP Foundation for financial support
(APP1101258, IH150100028).

Conflict of interest

Authors declare no conflict of interest.

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Author details

Huan Wu1, Michael Wallach2 and Olga Shimoni1*

1 Faculty of Science, Institute for Biomedical Materials and Devices, University of

Technology Sydney (UTS), Ultimo, New South Wales, Australia

2 Faculty of Science, School of Life Sciences, University of Technology Sydney,

Ultimo, New South Wales, Australia

*Address all correspondence to: [email protected]

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

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Celiac Disease - From the Bench to the Clinic

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