Journal of Crohn's and Colitis, 2020, 1–10

doi:10.1093/ecco-jcc/jjaa093
Advance Access publication May 11, 2020
Review Article

Review Article

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A Practical Guide for Faecal Calprotectin
Measurement: Myths and Realities
Ferdinando D’Amicoa,b, Stéphane Nanceyc, Silvio Danesea,d,
Laurent Peyrin-Birouletb
a
Department of Biomedical Sciences, Humanitas University, Milan, Italy bDepartment of Gastroenterology and Inserm
NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France cDepartment of
Gastroenterology, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre Benite, and Inserm U1111, CIRI, Lyon, France
d
IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano -IRCCS-, Milan, Italy

Corresponding author: Prof. Laurent Peyrin-Biroulet, MD, PhD, Inserm NGERE and Department of Gastroenterology, Nancy
University Hospital, University of Lorraine, 1 Allée du Morvan, 54511 Vandoeuvre-lès-Nancy, France. Tel: (+33) 383153661;
Fax: (+33) 383153633; E-mail: peyrinbiroulet@gmail.com

Abstract
Background and Aims: Faecal calprotectin [FC] is a valid and non-invasive marker of mucosal
inflammation. It is widely used both in clinical trials and in daily clinical practice for patients with
inflammatory bowel diseases, but currently no accepted standardization for FC testing is available.
Our primary aim here was to provide a clinician’s guide containing all the practical information on
FC measurement in order to avoid any confounding factors, to minimize intra- and inter-individual
variability in dosage, and to ensure a better and adequate interpretation of the results.
Methods: We conducted a detailed search of the scientific literature in the PubMed/MEDLINE,
EMBASE and Cochrane databases up to January 2020 to find all relevant and available articles on
pre-analytical and analytical phases of FC measurement.
Results: FC testing is a multi-step procedure consisting of a pre-analytical phase aimed to collect
and process the stool sample and a subsequent analytical phase of FC measurement. Several
factors can influence test results determining false positives or false negatives. Importantly, this
faecal marker is mostly used for patient follow-up and as a predictor of treatment response. For
this reason, any altered data may affect the physicians’ decisions, negatively impacting on patient
management.
Conclusions: This review provides for the first time practical advice to minimize dosage variability,
although further dedicated studies are needed to compare commercially available tests and
identify the best tools for the most precise and accurate FC measurement.

Key Words: Faecal calprotectin; guide; inflammatory bowel disease

1. Introduction status5 and to assess disease activity. Acute intestinal inflammation

is mainly characterized by an infiltrate of macrophages and neu-
Colonoscopy is currently the gold standard1 for monitoring disease
trophils inside the mucosa.6,7 These immune cells release cytosolic
activity in patients with inflammatory bowel disease [IBD] allowing
proteins, which can be detected in the faeces and are predictive of
both macroscopic and microscopic assessment.2 However, endo-
inflammation.5 Calprotectin is a calcium and zinc binding protein
scopic procedures are relatively invasive, expensive, time-consuming,
and constitutes about 60% of the neutrophil cytosolic proteins.8
uncomfortable and poorly tolerated by patients.3,4 For this reason,
Calprotectin is synthesized during inflammatory processes and it has
surrogate outcomes have been proposed to detect the inflammatory

© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.
1
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2
anti-microbial and anti-proliferative functions, having a regulatory
role on inflammation.9–11 Faecal calprotectin [FC] measurement is
a non-invasive marker of gut inflammation.12 It is significantly cor-
related with endoscopic and histological inflammation and is useful
for the diagnosis and follow-up of patients with IBD, allowing us
to distinguish active from inactive disease, to predict possible re-
lapses, and also to monitor response to treatment.13–18 Currently,
the Selecting Therapeutic Targets in Inflammatory Bowel Disease
[STRIDE]19 recommendations do not include FC among the treat-
to-target in patients with IBD. However, as revealed by the random-
ized phase III study on tight control management of patients with
CD [CALM study],20 the therapeutic decisions guided by the com-
bination of clinical symptoms and biomarkers [FC and serum C re-
active protein] result in better clinical and endoscopic outcomes than
decisions based solely on patients’ symptoms. Importantly, a meta-
analysis showed that FC measurement as a screening tool for IBD
could reduce the number of colonoscopies by 67% in adult patients
and by 65% in children and adolescents, considerably impacting on
healthcare costs.21 However, several pre-analytical [e.g. timing of
sampling, stool storage and stool weight] and analytical [e.g. types of
FC measurement kits] variables can modify the results of FC testing,
making the measurements heterogeneous at an intra-individual level
and from centre to centre22 [Figure 1]. Although numerous studies
Pre-analytical phase
1. Timing 2. Collection
Analytical phase
1. ELISA assay 2. Point-of-care rapid tests
Figure 1. Steps of the pre-analytical phase and types of FC measurement kits during the analytical phase.
Ferdinando D’Amico et al.
have been carried out on this topic and several schemes have been
proposed to homogenize the measurements, there is still no clear
standardization on FC testing.23–26 The primary aim of this review
is to provide for the first time a guide containing all the practical
information on FC measurement in order to avoid any confounding
factors, to minimize the variability of the dosage and to ensure a
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better interpretation of the results.
1.1. Search strategy and selection criteria
We conducted a detailed search of the scientific literature in the
PubMed/MEDLINE, EMBASE [Excerpta Medica Database] and
Cochrane databases up to January 2020 to find all relevant and
available articles on the pre-analytical and analytical phases of FC
dosage. The following search terms were used alone or in combin-
ation: ‘faecal calprotectin’, ‘dosage’, ‘pre-analytical phase’, ‘ana-
lytical phase’, ‘enzyme-linked immunosorbent assay’, ‘ELISA’,
‘point-of-care test’, ‘stool sampling’, ‘inflammatory bowel disease’,
‘IBD’, ‘ulcerative colitis’ and ‘Crohn’s disease’. The search focused
on full-text papers published in English, but abstracts were also
considered when relevant. No publication date restrictions were im-
posed. Further studies were selected after careful evaluation of the
bibliographic lists of the included articles. All authors were involved
in drafting the manuscript and agreed with its final version.
3. Storage 4. Extraction
3. Home testing
Practical Guide for Faecal Calprotectin Measurement
2. Results
In total, 2423 articles were obtained from our research [PubMed/
MEDLINE: 1574; EMBASE: 451; Cochrane database: 398]. After
careful evaluation and collegial discussion, all studies considered
relevant by the authors were included in the work in order to define
acceptable statements for FC measurement. The statements for the
pre-analytical and analytical phases of FC dosage are summarized
in Table 1.
2.1. Pre-analytical phase
2.1.1. Stool sampling
Stool sample collection should be performed at home and then sent
to the laboratory, although some new methods allow the analysis
of the sample even at home.27,28 About 100 mg of faeces is required
for proper FC measurement.27 Stool consistency can influence the
level of FC and sampling of normally formed faeces should be pre-
ferred.29 Stools should be collected in dedicated clean containers
without additives, avoiding any accidental contamination with urine
or water.27
2.1.2. Timing of sampling
The optimal timing for stool sampling is od debate. A prospective
study29 including patients with active ulcerative colitis [UC] analysed
FC values at different time points and showed that FC levels were
not correlated with faeces concentration. However, a significant
difference in FC values was found between several measurements
during the day and between one day and another, emphasizing a
high variability. Furthermore, it was observed that the time between
bowel movements was related to FC values [the greater temporal
distance and the greater FC concentration]. It was therefore assumed
that FC measurements should made during the first morning defe-
cation, especially in patients who generally did not have nocturnal
evacuations. Nevertheless, a study by Calafat et al.30 assessing FC
Table 1. Statements for the pre-analytical and analytical phases of
faecal calprotectin [FC] measurement
Pre-analytical phase
Stool sampling • Stool sample collection should be performed at
home
• At least 100 mg of faeces should be collected
• Normally formed faeces should be preferred
• Any contamination of the stool sample should be
avoided
Timing of sam- • The first morning sample is generally collected
pling • The analysis of only one stool sample is sufficient
• Repetition of FC measurement after a few days is
not recommended
Stool storage • In the laboratory the samples should be stored
in a freezer at −20°C and should be processed
within 3 days and no later than one week
FC extraction • The weighing technique is the gold standard
• A mix of four different extractions of the same
sample should be used for analysis
Analytical phase
FC measurement • Quantitative techniques are the gold standard
• The enzyme-linked immunosorbent assay is the
most appropriate test
• Point-of-care tests and home-based measurements
are valid alternatives
• Measurement should always be performed with
the same instrument
3
within-day variability documented that the first morning defeca-
tion had the highest FC values in only one-third of the samples;
the highest FC point was obtained with the second sample [44%],
showing that at present there is no clear benefit of using the first
morning faeces for FC analysis. In a prospective cohort study31
including 98 patients with Crohn’s disease [CD] low day-to-day
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variability was found among three different FC measurements.
However, in the study by Moum et al.32 a significant difference in
FC values was obtained in stool sample analyses from two consecu-
tive days in CD patients. Another prospective observational study33
showed a high daily variability in FC concentrations in both CD
and UC patients [ranging from 13% to 26%], suggesting that faeces
should preferentially be sampled in the morning to reduce any pos-
sible difference. Likewise, in a recent observational case-control
study34 intra-individual variability, which was defined as the differ-
ence in the FC values of the same individual between one day and
another, was significantly elevated in 27–58% of patients.34 Instead,
low intra-stool variability was reported, resulting in a uniform FC
distribution within the faeces. Another study by Kristensen et al.35
investigating both diurnal and day-to-day FC variability detected
a mean coefficient of variation of 39.4% (95% confidence interval
[CI] 31.1–47.7) at three different times of FC analysis [morning–
evening–morning] although the two measured variabilities were not
statistically significant. Overall, these data suggest that analysis of
only one stool sample should be sufficient for adequate FC evalu-
ation and that intra-individual variability should be considered in
the interpretation of measurement results.
2.1.3. Stool storage
FC is resistant to intestinal proteolysis remaining unchanged at room
temperature up to 3 days after sampling, while after 7 days a reduc-
tion in FC concentration of up to 28% is seen.29,36,37 Stool freezing38
has been proposed to counteract this progressive sample deterior-
ation, but a reduction in FC levels was found after 1 week of freezing
both at −20°C and at −80°C. Once in the laboratory faeces should
therefore be stored in a freezer at −20°C just after sample homogen-
ization and should be ideally processed within 3 days and no later
than 1 week.
2.1.4. Faecal calprotectin extraction
FC analysis is always preceded by a pre-treatment that allows ex-
traction of the calprotectin contained in the faeces followed by pla-
cing the sample in a buffer.39 During protein extraction a standard
quantity of faeces should be weighed and placed in the buffer. The
stool sample can be weighed manually, but it is preferable to use
dedicated devices, specific for each measurement kit, thus reducing
sample manipulation.39 Several extraction devices are commercially
available, although significant variability in their extraction capacity
based on stool consistency has been reported.40 A study by Juricic
et al.41 reported that FC concentrations differed significantly ac-
cording to the extraction method and stool consistency. Faeces, in
particular liquid faeces, should therefore be diluted in the extraction
buffer and eventually centrifuged, allowing the detection of sedi-
mented particles.27 Another important factor affecting the hetero-
geneity of FC results is the number of stool samples extracted and
used for analysis.42 A study by Pansart et al.42 showed significant dif-
ferences in FC values when the analysed sample was extracted from
a single location. To overcome this limitation it is recommended to
use a mix of four different extractions of the same sample to opti-
mize the FC measurement.42 In addition, freezing may alter the neu-
trophil membrane resulting in increased FC release, but in a study
4
including 75 IBD patients43 no difference in FC values was found in
faecal samples analysed after freezing.
3. Analytical Phase
FC results from randomized clinical trials are reported in Table 2.
FC is measured by various immunochemical methods through
monoclonal or polyclonal antibodies targeting different calprotectin
epitopes.39 FC testing can be performed using quantitative or quali-
tative techniques: the former measure the quantity of calprotectin
present in the faeces, while the latter simply express a positive or
negative test result. Qualitative analysis has weak clinical value, and
therefore most of the kits use quantitative analysis.38 The enzyme-
linked immunosorbent assay [ELISA] is the standard quantitative test
and is the most widely used tool for FC measurement. The majority
of commercially available tests use a cut-off of 50 μg/g to distinguish
normal from altered FC values.44 However, this technique is time-
consuming and in most laboratories it is performed as a batch-like
procedure every 1 or 2 weeks to reduce its costs.45 The commercially
available ELISA tests can be carried out manually or semi-automated
through various ELISA platforms. Interestingly, several automated
ELISA tests based on fluorescence [fluoro-enzyme immunoassays,
FEIA], chemi-luminescence [chemi-luminescence immunoassays,
CLIA], or immune-turbidimetry [particle-enhanced turbidimetric im-
munoassays, PETIA] have recently been developed.39 In contrast to
the traditional ELISA tests that analyse only 35–40 samples at a time,
these new tests allow the stool samples to be processed at any time,
even individually, reducing the analysis time.39 Point-of-care [POC]
rapid tests [e.g. Quantum Blue] have been developed to overcome
the problems related to ELISA tests. They use lateral flow immune-
chromatography to obtain a quantitative or semi-quantitative dose
of calprotectin within 30 min.27 These tools proved to be accurate
for predicting endoscopic disease activity in patients with active
IBD46 and the agreement between POC and ELISA test results was
good, suggesting that POC tests can be adopted when a rapid re-
sult of FC dosage is required.47,48 Furthermore, a new method [e.g.
IBDoc, QuantonCal and CalproSmart] for measuring FC levels at
the patient’s home has been proposed and validated.49 A smartphone
application scans the test cassette and calculates calprotectin con-
centrations allowing the patient and the physician to obtain respect-
ively qualitative and quantitative results immediately.50 This new
tool proved to have good accuracy and intra-/inter-assay coefficient
of variation [4.42% and 12.49%, respectively] and was positively
correlated with ELISA methods [r = 0.87].50 Moreover, this method
solves the problem of sample transport to the laboratory, improving
dosage acceptability for patients.51 Unfortunately, these instruments
Table 2. Faecal calprotectin values from randomized clinical trials
First author Study drug Study population Number of patients FC kit
D’Haens105 IFX CD 122
De Vos106 IFX UC 113
Colombel20 ADA CD 244
Assa107 ADA CD 78
Sandborn108 VDZ CD 1115
Reinisch VDZ UC 895
Feagan109 UST CD 1369
Sandborn97 TOFA UC 194
UC: ulcerative colitis; CD: Crohn’s disease; /: not reported; TOFA: tofacitinib; VDZ: vedolizumab; ADA: adalimumab; UST: ustekinumab, IFX: infliximab.
Ferdinando D’Amico et al.
for FC measurement are not interchangeable for FC monitoring and
as demonstrated by several studies there is a high variability between
the available methods. A Danish study52 including 148 patients com-
pared the accuracy of three ELISA tests [EK-CAL, CALPRO and
HK325] showing that the CALPRO test was the most specific in
detecting IBD [Table 3]. A comparative study53 investigated the
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accuracy of six different automated FC immunoassays [Thermo
Fisher EliA Calprotectin 2 assay, Diasorin Calprotectin assay, Inova
QUANTA Flash Calprotectin, Bühlmann fCAL Turbo, Euroimmun
Calprotectin assay and Orgentec Calprotectin assay] for the diag-
nosis of IBD. All the examined assays had excellent diagnostic ac-
curacy with areas under the curves [AUC] ranging from 0.974 to
0.998, without significant variation between the methods. However,
quantitative analysis showed substantially different concentrations
between several techniques. Whitehead et al.40 compared the per-
formance of three ELISA kits [Immunodiagnostik, Buhlmann and
Eurospital] and three extraction devices [Roche, Immunodiagnostik
and ScheBo Biotech] to assess intestinal inflammation. The study re-
vealed up to 3.8-fold differences between different ELISA tests and
an FC under-recovery rate ranging between 7.8% and 28.1% with
the used extraction devices compared to the manual weighing tech-
nique. Labaere et al.44 evaluated six FC assays: three rapid immune-
chromatographic assays [Buhlmann Quantum Blue, Eurospital
Calfast, Biotec Certest], two ELISAs [Eurospital and Calprolab] and
one automated immunoassay [Phadia EliA]. Different FC values
were found from analysis of the same stool sample with these kits.
FC testing should therefore always be performed with the same
instrument in order to overcome the problem of measurement
heterogeneity.
3.1. Factors influencing FC measurement
3.1.1. Factors associated with an increase in FC levels
The factors associated or not with an increase in FC levels are shown
in Table 4. FC measurement predicts the presence of gut inflamma-
tion, but it is not specific for IBD. Several factors can influence FC
levels. Elevated FC values can be found in patients with colorectal
neoplasms.54 In a study by Tibble et al.,55 90% of patients with
colorectal cancer had positive FC results. Colon polyps,56,57 colonic
diverticular disease,58 both bacterial59 and viral60 gastrointestinal
infections, irritable bowel syndrome [IBS],61 microscopic colitis,62
proctitis after radiation therapy,63 and pouchitis64 have also been as-
sociated with an increase in FC values. High FC values have also
been found associated with liver cirrhosis complications [enceph-
alopathy and spontaneous bacterial peritonitis]65,66 and in patients
with lung infections67,68 probably as a result of an altered intestinal
microbiota and subsequent bacterial translocation. A randomized
FC cut-off (µg/g) FC interpretation
Quantum Blue test 250 Disease activity evaluation
/ 300 Relapse prediction
/ 250 Disease activity evaluation
/ 150 Disease activity evaluation
/ 250 Disease activity evaluation
CALPRO Calprotectin ELISA 150 Disease activity evaluation
Test
/ 250 Disease activity evaluation
Enzyme-linked immunosorbent 150 Disease activity evaluation
assay [PhiCal]
Practical Guide for Faecal Calprotectin Measurement 5

Table 3. Operating characteristics of different faecal calprotectin tests

First author Study population FC test FC cut-off Situation SE SP PPV NPV LR+ LR-
(µg/g) predicted (%) (%) (%) (%) (%) (%)

Kwapisz et al.46 126 patients with Quantum Blue 100 Endoscopic 83 67 65 85 1 /

LGI symptoms Buhlmann disease activity

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Vinding et al.50 115 UC patients CalproSmart 150 Intestinal 82 85 47 97 5.51 0.21
106 CD patients home test inflammation
Mirsepasi- 96 IBD patients EK-CAL 50 Clinical 92 74 / / / /
Lauridsen 52 healthy CALPRO 50 disease activity 90 93 / / / /
et al.52 controls HK325 50 92 74 / / / /
Oyaert et al.53 15 CD patients EliA 50 Diagnosis of 100 66.2 / / 0.41 0.0
12 UC patients Calprotectin 2 50 IBD 100 78.5 / / 1.2 0.0
78 control pa- Diasorin 50 100 72.9 / / 0.43 0.0
tients Calprotectin 50 100 66.2 / / 0.14 0.0
Inova Quanta 50 100 58.4 / / 0.21 0.0
Flash 50 100 58.6 / / 0.0 0.0
Bühlmann
fCAL Turbo
Euroimmun
Calprotectin
Orgentec
Calprotectin
Labaere et al.44 31 suspected IBD Calprolab 50 Diagnosis of 83 89 83 89 7.9 0.19
patients Quantum Blue 50 IBD 83 68 63 87 2.7 0.24
31 IBD patients Buhlmann 70 82 88 82 88 6.9 0.21
Calfast 50 82 88 82 88 6.9 0.21
Calprest 50 75 95 90 86 14.3 0.26
Phadia EliA 50 83 84 77 89 5.3 0.20
Certest

FC: faecal calprotectin; CD: Crohn’s disease; UC: ulcerative colitis; IBD: inflammatory bowel disease; SE: sensibility; SP: specificity; PPV: positive predictive
value; NPV: negative predictive value; LR-: negative likelihood ratios; LR+: positive likelihood ratios; /: not reported; LGI: lower gastrointestinal.

trial studied the effects of blood on FC concentrations.69 Sixteen
healthy volunteers with normal FC levels [defined as FC < 50 µg /g]
were enrolled. Patients were randomized to ingest 100 or 300 mL of
their own blood and subsequently FC was dosed at different time
points. Overall positive values were found in 10/16 patients [63%]
in the 300-mL group and in 7/15 patients [46%] in the 100-mL
group, although no patient had FC > 300 µg/g. Therefore, FC dosage
should not be performed immediately after episodes of menstrual or
nasal bleeding.70 In addition, some drugs can be related to FC modi-
fications. A rheumatological study71 showed that patients treated
with non-steroidal anti-inflammatory drugs [NSAIDs] for at least
1 month had significantly higher FC values compared to the con-
trol group. Interestingly, no significant difference was found between
several types and doses of NSAIDs or by comparing users and non-
users of gastro-protective drugs (proton pump inhibitor [PPI], H2
antagonist or misoprostol). These data were confirmed by a study72
on healthy volunteers showing that 75 mg of diclofenac twice daily
for 2 weeks was associated with a significant increase in FC concen-
trations [from 11 to 82 µg/g, p < 0001]. NSAIDs should therefore be
stopped at least 2 weeks before sampling.27 PPI therapy can also sub-
stantially modify FC levels. Patients treated with PPI had a signifi-
cant increase in FC values compared to patients without PPI [78.16
vs 30.9 µg/g; p < 0.0001].73 Increased FC levels were also detected
in a study on chronic gastritis.74 PPI users had higher FC levels than
PPI non-users, although this difference was not statistically signifi-
cant [32.88 vs 25.64 µg/g; p > 0.05]. Hence, PPIs should ideally be
discontinued 4 weeks75 before measuring calprotectin and the use of
these drugs considered in the interpretation of FC results. Moreover,
it has been hypothesized that age may affect FC concentrations.
A British study76 on healthy subjects showed that paediatric patients
[2–9 years] had higher FC values compared to patients aged 10–59
and > 60 years [34, 22 and 27 µg/g respectively, p < 0.05 for both
comparisons]. Interestingly, in a paediatric study by Lee et al.,77 in-
fants younger than 6 months had abnormal mean FC levels [322,
197 and 111 µg/g at 0–2, 3–4 and 5–6 months, respectively] and
these values normalized over time. Furthermore, infants born via
normal spontaneous vaginal delivery and those who were breastfed
had higher FC concentrations than those born by caesarean section
and fed with formula milk [319 and 354 µg/g vs 130 and 149 µg/g,
respectively]. A Swedish retrospective study78 also showed that pa-
tients older than 65 years had an increase in FC levels [>100 µg/g] in
about 20% of cases. Additionally, lifestyle factors, including obesity
and physical inactivity, were significantly associated with alterations
in FC concentrations.79 In addition, a paediatric study80 found con-
siderable variability in FC levels after bowel preparation for colon-
oscopy. FC sampling should therefore be performed before starting
intestinal preparation or at least 48 h after the endoscopic procedure
in order not to affect FC measurement.
3.1.2. Factors not associated with an increase in FC levels
A Norwegian study36 tested the effect of several drugs commonly
used in gastroenterology [mesalazine, sulfasalazine, metronidazole,
sucralfate, cholestyramine, prednisolone, azathioprine, metho-
trexate, cyclosporine], nutraceuticals [multivitamin and iron sup-
plements] and foods [bread and minced steak] for interference with
calprotectin, and found no correlation. A retrospective study81 in-
vestigated the influence of disease location on FC levels, detecting
different FC values in patients with isolated small bowel CD and
6 Ferdinando D’Amico et al.

Table 4. Factors associated and not associated with an increase in highlighted, FC can also be used to assess the disease activity of IBD
faecal calprotectin levels patients and to guide therapeutic decisions.13,14 Importantly, the as-
sociation between colic inflammation and FC elevation in CD pa-
Factors associated with an increase Factors not associated with an
in FC levels increase in FC levels tients is well established,91 while there are some concerns about the
diagnostic accuracy of FC in subjects with ileal disease.82 In fact,
Gastrointestinal diseases Drugs there is evidence that some patients with ileal ulcers have normal

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• Colorectal neoplasia • Mesalazine FC values, resulting in false negatives.92 Although an association be-
• Colon polyps • Sulfasalazine tween disease location [colon vs ileum] and FC levels in CD patients
• Colonic diverticular disease • Metronidazole has been suggested, it is not known whether FC cut-offs should be
• Bacterial and viral • Sucralfate
different in patients with ileal or colic disease.85 On the other hand,
gastrointestinal infections • Cholestyramine
it is necessary to distinguish between operated and non-operated pa-
• Gastrointestinal bleeding • Prednisolone
• Liver cirrhosis • Azathioprine
tients. In operated patients it may be useful to adopt a low FC cut-off
• Irritable bowel syndrome • Methotrexate [100 µg/g]91,93 in order to identify any disease recurrence at an early
• Microscopic colitis • Cyclosporine stage, while in non-operated patients a high cut-off could be selected
• Proctitis after radiation therapy [250 µg/g].20 In case of clinical symptoms and increased FC values,
• Pouchitis a second FC testing or endoscopic/radiological investigations [mag-
Drugs μ netic resonance or small bowel ultrasound] should be performed [if
• Non-steroidal anti-inflammatory a long time has passed since the last diagnostic assessment] to con-
drugs firm the presence of inflammation and to specify the type, severity
• Proton pump inhibitors
and location of the lesions.24 Importantly, high C-reactive-protein
Lifestyle Lifestyle
[CRP] values [>10 mg / L],94 in the absence of acute infections, could
• Obesity • Diet [bread and minced steak]
• Physical inactivity
further confirm the presence of inflammation in patients with in-
Other Other creased FC levels, justifying therapeutic optimization without add-
• Age < 9 years • Pregnancy itional invasive investigations. Nowadays, although the optimal
• Age > 65 years • Disease location timing for FC measurement is not known and there is no standard-
• Bowel preparation for • Nutraceuticals [multivitamin ization, an FC test should be performed every 3–6 months for active
colonoscopy and iron supplements] disease follow-up and every 6–12 months during disease remis-
• Lung infections sion.95 In patients with UC, FC was shown to be closely correlated
to endoscopic12 and histological96 activity of disease. An FC value
FC: faecal calprotectin. >250 µg/g is associated with mucosal disease activity [endoscopic
Mayo score ≥ 1],12 a cut-off point of 150 µg/g97 could be useful to
between UC patients with proctitis or with left-sided colitis/pancolitis. identify patients with mucosal healing [endoscopic Mayo 0], while a
Similarly, a study by Zittan et al.82 showed a significant correlation negative FC value [<100 µg/g] could predict histological healing.15,98
between FC and endoscopic findings in CD patients with colonic Special situations such as pouchitis and proctitis deserve particular
involvement, while no correlation was found in subjects with small attention. In fact, in patients with pouchitis, FC was shown to be
bowel CD. On the other hand, a prospective multi-centre study83 re- closely related to endoscopic and histological findings and an FC
vealed no statistically significant difference in FC concentrations be- value of 100 µg/g could allow early detection of patients with mu-
tween patients with ileal or colonic CD, and a study by Gecse et al.84 cosal or microscopic inflammation and early management of pos-
confirmed that disease location was not associated with differences sible relapses.99,100 In addition, FC was more sensitive than CRP in
in FC values. A recent systematic review85 including 16 studies tried predicting endoscopic disease activity in both CD and UC101. Unlike
to resolve doubts about the relationship between disease location blood biomarkers, FC was not affected by disease extent [proc-
and FC values, but data heterogeneity did not allow the authors to titis, left-sided colitis or pancolitis]102 and it should be preferred in
draw definitive conclusions. Finally, the role of FC during pregnancy the assessment of patients with proctitis, using an FC threshold of
has been debated for a long time. A Danish nationwide cohort86 of 100 µg/g. Finally, FC has gained increasing clinical relevance as it
219 pregnant women with moderate-to-severe IBD treated with is closely related to clinical, endoscopic and histological findings in
anti-tumour necrosis factor α [anti-TNF α] drugs reported that FC IBD patients.96 In recent years, imaging findings have proved to be
levels were correlated with disease activity; patients with active dis- accurate in monitoring disease activity.103 Radiological response had
ease had significantly higher FC concentrations compared to those in a significant impact on both short- and long-term outcomes of CD
clinical remission [p < 0.003]. Two prospective studies87,88 including patients, suggesting transmural healing [TH] as a promising new
pregnant women with IBD found no variation in FC points during treat to target.19,103,104 In the near future, specifically designed trials
pregnancy, suggesting that the physiological modifications involving will be necessary to evaluate the correlation between TH and FC in
pregnant women do not influence FC. Accordingly, FC could be used order to identify an FC value predictive of radiological remission.
as a valid marker to monitor disease activity during pregnancy.

3.2. Proposed algorithm for FC interpretation in 4. Conclusion

clinical practice
FC is an accurate tool to investigate gut inflammation and its testing
plays a key role in distinguishing IBD from IBS, as these diseases
share some symptoms including abdominal pain and diarrhoea.89
An FC level of 50 µg/g could be a valid cut-off to differentiate be-
tween organic and functional pathologies90 [Figure 2]. As previously
The standardization of FC measurement is essential to best manage
patients with IBD. The pre-analytical phase plays a fundamental
role and each step of this process must be correctly performed from
timing to sampling, from storage to extraction, in order to reduce
evaluation bias and obtain more reliable results to adequately guide
physicians’ decisions. The standard technique for the analytical
Practical Guide for Faecal Calprotectin Measurement 7

IBS vs IBD Crohn’ disease Ulcerative colitis Special situations

Abdominal Pouchitis
pain Diarrhea 100 250 Histology
FC
Endoscopy

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Operated Non-operated
patients patients
FC FC 100
measurement

< > Increased FC CRP >10 mg/>L Endoscopy Histology

50
2° FC test Confirmation 250
Mayo score ≥1 Proctitis
Endoscopy Imaging

MRI US CRP FC
150
IBS CD UC
Consider Mayo score 0
therapy optimization
100

Histologic
100 remission

Figure 2. Interpretation algorithm for faecal calprotectin levels in patients with inflammatory bowel diseases.FC: faecal calprotectin; IBS: irritable bowel
syndrome; CD: Crohn’s disease; UC: ulcerative colitis; CRP: C reactive protein; MRI: magnetic resonance imaging; US: ultrasound.

phase remains the ELISA test, although rapid methods, which can
also be performed at the patient’s home, are available and of great
interest to improve acceptability by the patient. This review pro-
vides practical advice to minimize dosage variability, but further
dedicated studies are needed to compare commercially available
tests and identify the one that allows the more precise and accurate
measurement.
Funding
Gilead.
Conflict of Interest
F.D’A. declares no conflict of interest. S.N. has served as a speaker, con-
sultant and advisory board member for Merck, Abbvie, Janssen, Ferring,
Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Lilly, HAC- Pharma,
Amgen, Sandoz and Novartis. S.D. has served as a speaker, consultant and
advisory board member for Schering- Plough, AbbVie, MSD, UCB Pharma,
Ferring, Cellerix, Millenium Takeda, Nycomed, Pharmacosmos, Actelion,
Alphawasserman, Genentech, Grunenthal, Pfizer, Astra Zeneca, Novo
Nordisk, Cosmo Pharmaceuticals, Vifor, Johnson & Johnson, Nikkiso Europe
and Theravance. L.P.-B. has served as a speaker, consultant and advisory board
member for Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine,
Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boerhinger-
Ingelheim, Lilly, HAC- Pharma, Index Pharmaceuticals, Amgen, Sandoz,
Forward Pharma, Celgene, Biogen, Lycera, Samsung Bioepis and Theravance.
Author Contributions
F.D. wrote the manuscript. S.N. and S.D. critically reviewed the content of the
paper and supervised the project. L.P.B. conceived the study, contributed to
the critical interpretation of the results, and supervised the project. All authors
discussed the results and contributed to the final manuscript.
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