i1

European evidence based consensus on the diagnosis and

Gut: first published as 10.1136/gut.2005.081950a on 15 February 2006. Downloaded from [Link] on May 25, 2023 by guest. Protected by copyright.
management of Crohn’s disease: definitions and diagnosis
E F Stange, S P L Travis, S Vermeire, C Beglinger, L Kupcinskas, K Geboes, A Barakauskiene,
V Villanacci, A Von Herbay, B F Warren, C Gasche, H Tilg, Stefan W Schreiber, J Schölmerich,
W Reinisch, for the European Crohn’s and Colitis Organisation (ECCO)
...............................................................................................................................

Gut 2006;55(Suppl I):i1–i15. doi: 10.1136/gut.2005.081950a

1.0 INTRODUCTION consensus, as well as diagnosis, pathology, and
classification of CD. The second section on
Crohn’s disease (CD( is a lifelong disease arising
current management includes treatment of
from an interaction between genetic and envir-
active disease, maintenance of medically induced
onmental factors, but seen predominantly in the remission, and surgery of CD. The third section
developed countries of the world. The precise on special situations in CD includes postopera-
aetiology is unknown and therefore a causal tive recurrence, fistulating disease, paediatrics,
treatment is not yet available. Within Europe pregnancy, psychosomatics, extraintestinal man-
there is a distinct north-south gradient, but the ifestations, and alternative therapy.
incidence seems to have increased in southern The strategy to reach the consensus involved
countries in recent years.1 Many patients live five steps:
with a considerable symptom burden despite
medical treatment in the hope that the aetiology (1) Relevant questions on each of 14 separate
of the disease will shortly be discovered and topics concerning diagnosis and treatment of
curative therapies emerge. Although this seems CD were devised by the chairmen and their
likely to happen at some time in the next decade, working party. The questions were focused
clinicians have to advise patients on the basis of on current practice and areas of controversy
information available today rather than an in the task force topic, sent around to the
unknown future. Despite a multiplicity of ran- other chairmen to avoid duplication, and
domised trials there will always be many ques- then to all participants in the consensus
tions that can only be answered by the exercise conference. Participants were asked to
of judgement and opinion. This leads to differ- answer the questions based on their experi-
ences in practice between clinicians, which may ence as well as evidence from the literature
be brought into sharp relief by differences in (Delphi procedure).4
emphasis between countries. (2) In parallel, the working parties performed a
The consensus endeavours to address these systematic literature search of their topic
differences. The consensus is not meant to with the appropriate key words using
supersede the guidelines of different countries Medline/Pubmed and the Cochrane data-
(such as those from the UK,2 Germany,3 or base, as well as their own files. The evidence
France), which reach broadly the same conclu- level was graded (table 1.1) according to the
sions as they are, after all, based on the same Oxford Centre for Evidence Based Medicine.5
evidence. Rather, the aim of the consensus is to
(3) Provisional guideline statements on their
promote a European perspective on the manage-
topic were then written by the chairmen,
ment of CD and its dilemmas. As the develop-
based on answers to the questionnaire as
ment of guidelines is an expensive and time
well as the literature evidence and were
consuming process, it may help to avoid duplica-
circulated first among the working party and
tion of effort in the future. A consensus is also
then among the participants.
See end of article for considered important because an increasing
authors’ affiliations number of therapeutic trials are based in (4) The working parties then met in Prague on
....................... Europe, especially in eastern European countries the 23 September 2004 to agree the state-
where practice guidelines have yet to be pub- ments. On 24 September 61 participants
Correspondence to:
Dr S P L Travis, John lished. gathered under the chairmanship of E F
Radcliffe Hospital, Oxford This document sets out the current European Stange to agree the final version of each
OX3 9DU, UK; [Link]- consensus on the diagnosis and management of guideline statement. Technically this was
vis@[Link]; Professor done by projecting the statements and
E F Stange, Department of CD, reached by the European Crohn’s and Colitis
Organisation (ECCO) at a meeting held in revising them on screen until a consensus
Internal Medicine 1, Robert
Bosch Krankenhaus, PO Prague on 24 September 2004. ECCO is a forum was reached. On one occasion, when the
Box 501120, Auerbachstr for specialists in inflammatory bowel disease ECCO Board considered that a statement
110, 70341 Stuttgart,
Germany; Eduard. (IBD) from 20 European countries. It was
Stange@[Link] established in 2000 with the common purpose
of promoting European views, clinical trials, and
Received specialist training in inflammatory bowel dis- Abbreviations: CD, Crohn’s disease; CDAI, Crohn’s
12 September 2005 disease activity index; CRP, C reactive protein; CT,
ease. The consensus is grouped into three parts:
Revised 18 December 2005 computed tomography; ECCO, European Crohn’s and
Accepted definitions and diagnosis; current management; Colitis Organisation; ESR, erythrocyte sedimentation rate;
21 December 2005 and management of special situations. This first IBD, inflammatory bowel disease; UC, ulcerative colitis;
....................... section concerns aims and methods of the US, ultrasound; WCE, wireless capsule endoscopy

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i2 ECCO consensus on Crohn’s disease

was open to misinterpretation and failed accurately to 1.1.1 Active disease

reflect the text, all original participants were asked to For the purposes of this consensus, clinical disease activity is
vote on new wording by email. Consensus was defined as grouped into mild, moderate, and severe (table 1.2). These are

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agreement by .80% of participants, termed a consensus not precisely defined entities. Most clinical trials in patients
statement and numbered for convenience in the docu- with active CD recruit patients with a Crohn’s disease activity
ment. Each recommendation was graded (RG) according index (CDAI) .220. The fallibility of this threshold is illustrated
to the Oxford Centre for Evidence Based Medicine,5 based by the high placebo response in recent trials of biological
on the level of evidence (table 1.1). therapy6 and the trend is now to use a CRP .10 mg/l in
(5) The final document on each topic was written by the conjunction with the CDAI. Remission (see below) is widely
chairmen in conjunction with their working party. accepted as a CDAI ,150 and response is increasingly defined
Consensus guideline statements displayed in boxes are as a decrease in CDAI >100 points. It would make sense to
followed by comments on the evidence and opinion. define disease activity in groups of 100 points, at least until a
Statements are intended to be read in context with sensitive, responsive, and validated index superior to the CDAI
qualifying comments and not read in isolation. The final is developed.7 This is an inconsistency that needs to be resolved,
text was edited for consistency of style by S P L Travis but until it can be modelled on clinical trial datasets disease
and E F Stange before being circulated and approved by activity is generally graded as in table 1.2.
the participants. In some areas the level of evidence is
generally low, which reflects the paucity of randomised 1.1.2 Remission
controlled trials. Consequently expert opinion is included The criterion used in most clinical trials when selecting CD
where appropriate. patients in clinical remission is a CDAI ,150.8 This has
become the customary definition and is accepted for the
purposes of evaluating the literature and clinical trials for as
1.1 Definitions long as the CDAI remains the principal index for evaluating
Common agreement was reached about frequently used outcome in trials of CD. In several studies, a biological index
terms. While the significance of some terms (such as ‘‘early’’ of Brignola ,100.9 10 was also a requirement. This has the
or ‘‘pattern of relapse’’) are undetermined, such terms reflect advantage of objectivity, but is not used in clinical practice. In
clinical decision making (such as when to start immunomo- keeping with the views of the International Organisation for
dulators). The arbitrariness of some of the definitions is the study of Inflammatory Bowel Disease, ECCO believes that
recognised, but the consensus considers it useful to agree the studies evaluating the maintenance of remission in CD
terminology. should last at least 12 months.8

Table 1.1 Levels of evidence and grades of recommendation based on the Oxford Centre for Evidence Based Medicine
Level Individual study Technique

1a Systematic review (SR) with homogeneity of level 1 Systematic review (SR) with homogeneity of randomised controlled trials (RCTs)
diagnostic studies
1b Validating cohort study with good reference standards Individual RCT (with narrow confidence interval)
1c Specificity is so high that a positive result rules in the All or none
diagnosis (‘‘SpPin’’) or sensitivity is so high that a negative
result rules
out the diagnosis (‘‘SnNout’’)
2a SR with homogeneity of level .2 diagnostic studies SR (with homogeneity ) of cohort studies
2b Exploratory cohort study with good reference standards Individual cohort study (including low quality RCT; for example, ,80% followup)
2c ‘‘Outcomes’’ research; ecological studies
3a SR with homogeneity of 3b and better studies SR with homogeneity of case-control studies
3b Non-consecutive study; or without consistently applied Individual case-control study
reference standards
4 Case-control study, poor or non-independent reference Case series (and poor quality cohort and case-control studies )
standard
5 Expert opinion without explicit critical appraisal, or based Expert opinion without explicit critical appraisal, or based on physiology, bench
on physiology, bench research, or ‘‘first principles’’ research, or ‘‘first principles’’
Grades of recommendation
A consistent level 1 studies
B consistent level 2 or 3 studies or extrapolations from level 1 studies
C level 4 studies or extrapolations from level 2 or 3 studies
D level 5 evidence or troublingly inconsistent or inconclusive studies of any level

For details see [Link]

Table 1.2 Grading of disease activity in Crohn’s disease

Mild Moderate Severe

Equivalent to a CDAI of 150–220 Equivalent to a CDAI of 220–450 Equivalent to a CDAI of .450

For example, ambulatory, eating and drinking, For example, intermittent vomiting, or weight loss For example, cachexia (BMI ,18 kg-2), or
,10% weight loss. No features of obstruction, fever, .10%. Treatment for mild disease ineffective, or evidence of obstruction or abscess. Persistent
dehydration, abdominal mass, or tenderness. CRP tender mass. No overt obstruction. CRP raised symptoms despite intensive treatment. CRP
usually increased above the upper limit of normal above the upperlimit of normal. increased.

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ECCO consensus on Crohn’s disease i3

1.1.3 Response 1.1.9 Recurrence

Response should be defined by a DCDAI >2100 points, The term recurrence is best used to define the reappearance
although in some studies, including those initially evaluating of lesions after surgical resection (while relapse refers to the

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the effectiveness of infliximab, a lesser end point of response reappearance of symptoms, above).
with a reduction in CDAI >70 points11 12 was used.
1.1.10 Morphological recurrence
The appearance of new CD lesions after complete resection of
1.1.4 Relapse
macroscopic disease, usually in the neo-terminal ileum and/
The term relapse is used to define a flare of symptoms in a
or at the anastomosis, detected by endoscopy, radiology, or
patient with established CD who is in clinical remission,
surgery.13 14 Endoscopic recurrence is currently evaluated and
either spontaneously or after medical treatment. Relapse is
graded according to the criteria of Rutgeerts et al (0: no
preferably confirmed by laboratory parameters, imaging, or
lesions; 1: less than five aphthous lesions; 2: more than five
endoscopy in clinical practice. For the purposes of
aphthous lesions with normal mucosa between the lesions, or
clinical trials a CDAI .150 with an increase of more than
skip areas of larger lesions, or lesions confined to the
70 points has been proposed.8 However, if a therapeutic
ileocolonic anastomotic lining (,1 cm); 3: diffuse aphthous
response is defined as a decrease in CDAI >100 points,
ileitis with diffusely inflamed mucosa; 4: diffuse ileal
then the definition would more rationally be a CDAI .150
inflammation with larger ulcers, nodules, or narrowing.
with an increase of 100 points from baseline. There is no Hyperaemia and oedema alone are not considered as signs of
international agreement on this, but future trials on CD recurrence).13
should take this into account. Other definitions (including
CDAI.150, or a CDAI.250, or an increase of 50 points if the 1.1.11 Clinical recurrence
baseline was between 150 and 250) are considered less The appearance of CD symptoms after complete resection of
acceptable. macroscopic disease, provided (for the purposes of clinical
trials) that recurrence of lesions is confirmed.14
1.1.5 Early relapse
An arbitrary, but clinically relevant period of ,3 months 1.1.12 Localised disease
after achieving remission on previous therapy defines early Intestinal CD affecting ,30 cm in extent. This usually applies
relapse. The therapeutic significance needs to be defined. to an ileocaecal location (,30 cm ileum ¡ right colon), but
could apply to isolated colonic disease, or conceivably to
proximal small intestinal disease.
1.1.6 Pattern of relapse
Relapse may be infrequent ((1/year), frequent (>2 relapses/ 1.1.13 Extensive Crohn’s disease
year), or continuous (persistent symptoms of active CD Intestinal Crohn’s disease affecting .100 cm in extent
without a period of remission). Although the terms are whatever the location. This applies to the sum of inflamma-
arbitrary, they are considered clinically relevant. The prog- tion in discontinuous segments. While there is clearly a ‘‘grey
nostic significance needs to be determined. area’’ of disease extent (between 30 and 100 cm) and the
The term ‘‘chronic active disease’’ has been used in the past length is arbitrary, this definition of extensive disease
to define a patient who is dependent on, refractory to, or recognises the greater inflammatory burden and implications
intolerant of corticosteroids, or who has disease activity for medical and surgical decision making with this extent of
despite immunomodulators. As this term is ambiguous it is disease.
best avoided. Instead, arbitrary, but more precise definitions,
are preferred, including corticosteroid refractory or corticos- 1.1.14 New patient
teroid dependence. A patient with active CD presenting at, or shortly after
diagnosis, with no previous therapy for CD.
1.1.7 Corticosteroid refractory disease
Patients who have active disease despite prednisolone up to 1.1.15 Alternative therapy
0.75 mg/kg/day over a period of four weeks. One that is used in place of conventional medicine.

1.1.16 Complementary therapies

1.1.8 Corticosteroid dependent disease Similar treatments used alongside conventional medicine
Patients who are either (see section on alternative therapies for comment).
(a) unable to reduce corticosteroids below the equivalent of 1.1.17 Expert opinion
prednisolone 10 mg/day (or budesonide below 3 mg/ The term ‘‘expert’’ is used here to refer to the opinion of the
day) within three months of starting corticosteroids, specialists in IBD representing multiple disciplines from 22
without recurrent active disease, or European countries who contributed to the ECCO Consensus.
(b) who have a relapse within three months of stopping In some sections opinions from individual members of other
corticosteroids. expert bodies were obtained, including members of the
European Society of Pathology (ESP) working group on
The assessment of corticosteroid refractoriness or depen- Digestive Diseases, or European Society of Gastrointestinal
dence should be made after careful exclusion of disease and Abdominal Radiology (ESGAR).
specific complications.
This definition of corticosteroid dependence requires that 2.0 CLINICAL DIAGNOSIS AND IMAGING
the total duration of corticosteroids does not exceed three CD most frequently presents in late adolescence or early
months before a threshold equivalent to prednisolone 10 mg/ adulthood and is equally distributed between the sexes.15
day is reached. Patients are still considered corticosteroid Symptoms at presentation vary depending on the location,
dependent if they relapse within three months of stopping behaviour, and severity of disease, as well as extraintestinal
corticosteroids. Although these limits are arbitrary, they serve manifestations and medication. The aim is to establish the
as guidance for clinical practice and may be used for diagnosis, and distribution of disease by appropriate techni-
uniformity in clinical trials. The aim should be to withdraw ques, as this influences the choice of treatment. The guidance
corticosteroids completely. on imaging reflects a gastroenterological perception on

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i4 ECCO consensus on Crohn’s disease

appropriate radiological techniques for patients with CD. colitis unclassified and the term indeterminate colitis
Although the European Society of Gastrointestinal and confined to operative specimens as originally described.27
Abdominal Radiology (ESGAR) was not officially involved The indiscriminate use of the term indeterminate colitis to
cover all cases of diagnostic uncertainty is confusing in the

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in the working party, the chairman (W Reinisch) consulted
frequently with C Bartram, a founding member of ESGAR, literature and imprecise in practice.
during the process of guideline preparation.
2.2.1 History and examination
2.1 Clinical features of CD
ECCO statement 2C
ECCO statement 2A
A full history should include detailed questioning about the
onset of symptoms, recent travel, food intolerances, contact
Symptoms of CD are heterogeneous, but commonly include
with enteric illnesses, medication (including antibiotics and
diarrhoea for more than six weeks, abdominal pain, and/or
non-steroidal anti-inflammatory drugs), smoking, family
weight loss. These symptoms should raise the suspicion of
history, and history of appendicectomy [EL5, RG D]
CD, especially in patients at young age. Systemic symptoms
of malaise, anorexia, or fever are common [EL5, RG D]

Chronic diarrhoea is the most common presenting symp- ECCO statement 2D

tom;16 17 a definition of a decrease in faecal consistency for
more than six weeks may be adequate to differentiate this Careful questioning about nocturnal symptoms, features of
from, self limited infectious diarrhoea.17 18 Abdominal pain extraintestinal manifestations involving the mouth, skin, eye,
and weight loss are seen in about 70% and 60% respectively or joints, episodes of perianal abscess, or anal fissure is
of patients before diagnosis. Blood and/or mucus in the stool appropriate. General examination includes general well-
may be seen in up to 40% to 50% of patients with Crohn’s being, pulse rate, blood pressure, temperature, abdominal
colitis, but less frequently than in ulcerative colitis (UC).17 tenderness or distension, palpable masses, perineal and oral
Abnormalities of the musculoskeletal system are the most inspection, and rectal digital examination. Measurement of
common extraintestinal manifestations of IBD, encompass- body weight and calculation of body mass index are
ing peripheral and axial joints.19 Extraintestinal manifesta- recommended [EL5, RG D]
tions are most common when CD affects the colon (see
section 12). Perianal fistulas are present in 10% of patients at
the time of diagnosis20 (see section 9). Smoking, prior appendicectomy, and a family history of IBD
have been reproduced as risk factors for the onset of CD.28 29
2.2 Diagnosis Retrospective studies on non-steroidal anti-inflammatory
drugs as a risk factor for CD are less consistent.30

ECCO statement 2B 2.2.2 Initial laboratory investigations

A single gold standard for the diagnosis of CD is not ECCO statement 2E

available. The diagnosis is confirmed by clinical evaluation
and a combination of endoscopic, histological, radiological, Check for signs of acute and/or chronic inflammatory
and/or biochemical investigations [EL5, RG D] response, anaemia, fluid depletion, and signs of malnutri-
tion/malabsorption [EL5, RG D]. Initial laboratory investiga-
tions should include CRP [EL2, RG B], and full blood count
[EL5, RG D]. If C reactive protein is not available, then
CD is a heterogeneous entity comprising a variety of complex measurement of the erythrocyte sedimentation rate (ESR) is
phenotypes.19 21 22 Originally, Dr Burrill Crohn and colleagues recommended [EL5, RG D]. Microbiological testing for
described regional ileitis as a chronic inflammatory disease infectious diarrhoea including Clostridium difficile toxin is
restricted to the terminal ileum in association with intestinal recommended [EL2, RG B]. Additional stool tests may be
stenoses or fistulas, but not crossing the ileocaecal valve.23 needed for patients who have travelled abroad. In a patient
The original concept has subsequently extended potentially to with a history consistent with CD, additional clinical and
affect the entire gastrointestinal tract.24–26 As there is no laboratory investigations are not necessary [EL5, RG D]
single way to diagnose CD, Lennard-Jones et al have defined
macroscopic and microscopic criteria to establish the diag-
nosis. The macroscopic features include physical examina- Anaemia and thrombocytosis represent the most common
tion, endoscopy, radiology, and examination of an operative changes in the full blood count in patients with CD. The C
specimen. Microscopic features can be only partly assessed on reactive protein (CRP) and erythrocyte sedimentation rate
mucosal biopsy, but completely assessed on an operative (ESR) are standard laboratory surrogates of the acute phase
specimen. The diagnosis depends on the finding of discon- response to inflammation. The CRP broadly correlates with
tinuous and often granulomatous intestinal inflammation.17 disease activity of CD assessed by standard indices and
The current view is that the diagnosis is established by a non- indicates serial changes in inflammatory activity because of
strictly defined combination of clinical presentation, endo- its short half life of 19 hours.31–36 The ESR less accurately
scopic appearance, radiology, histology, surgical findings and, measures intestinal inflammation in CD by reflecting
more recently, serology. This still results in diagnostic changes of plasma protein concentration and packed cell
obstacles. A change in diagnosis to UC during the first year volume. The ESR increases with disease activity, but
occurs in about 10%–15% of cases. IBD restricted to the colon correlates better with colonic rather than ileal disease.37
that cannot be allocated to CD or UC categories is best termed Neither of these parameters is specific enough to permit

[Link]
ECCO consensus on Crohn’s disease i5

differentiation from UC or enteric infection. Evidence for a Endoscopy and radiology are complementary techniques to
pathophysiological role of certain strains of luminal bacteria define the site and extent of disease, so that optimal therapy
in genetically susceptible hosts in CD comes from animal can be planned.46 48
models and studies on innate immunity. None yet have a

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diagnostic role. The value of routine stool examination in
patients with suspected CD or exacerbations of disease arises ECCO statement 2H
from both the differential diagnosis and high concordance
with enteric infections such as C difficile.38
Several techniques are used to investigate the small intestine
2.2.3 Procedures recommended to establish the including small bowel follow through, small bowel enema,
diagnosis transabdominal ultrasound, computed tomography (CT)-
enteroclysis (-graphy), and magnetic resonance imaging
(MRI)-enteroclysis (-graphy). For determination of extent and
ECCO statement 2F location of small bowel CD, most centres will perform either a
SBE or SBFT, with only some units undertaking CT- or MRI-
For suspected CD, ileocolonoscopy and biopsies from the enteroclysis (-graphy)
terminal ileum as well as each colonic segment to look for
microscopic evidence of CD are first line procedures to
establish the diagnosis [EL1b, RG A]
Fluoroscopic examinations (SBFT, SBE) are the current
standard for assessing the small intestine. These are
Colonoscopy with multiple biopsy specimens is well estab- ubiquitously available and permit a detailed analysis of the
lished as the first line procedure for diagnosing colitis.39–41 extent of diseased mucosal surface. Results of barium studies
Ileoscopy with biopsy can be achieved with practice in at least are, however, strongly influenced by the quality of the
85% of colonoscopies and increases the diagnostic yield of CD examination. Views may be obscured by overlying bowel
in patients presenting with symptoms of IBD.39 40 42 The most loops, while recognition of aphthoid ulceration requires good
useful endoscopic features of CD are discontinuous involve- compression. Cross sectional imaging (such as CT) provides
ment, anal lesions and cobble stoning. Colonoscopy predicts additional information on bowel wall thickening, associated
the anatomical severity of CD colitis with a high probability.43 changes in vascularity and in the adjacent mesentery, which
Anatomical criteria of severity are defined as deep ulcerations become more important as the severity of disease increases.
eroding the muscle layer, or mucosal detachments or The radiation burden from fluoroscopy and CT is appreciable,
ulcerations limited to the submucosa but extending to more so alternatives such as ultrasound (US) or MRI should be
than one third of a defined colonic segment (right, considered where possible.
transverse, left colon).43 When there is severe, active disease, Radiographic techniques for imaging the small intestine
the value of full colonoscopy is limited by a higher risk of may be divided into intubation (enteroclysis, CT- enteroclysis
bowel perforation41 and diagnostic errors are more frequent. and MRI-enteroclysis) and non-intubation studies. Non-
In these circumstances initial flexible sigmoidoscopy is safer intubation examinations include SBFT and oral preparations
and ileocolonoscopy postponed until the clinical condition for MR- or CT-enterography.49 50 Disagreement persists
improves.2 The scoring of endoscopic disease activity in CD is regarding the optimum fluoroscopic technique for small
reserved for clinical studies.8 Ileoscopy is superior for the bowel CD. Placement of a nasojejunal tube is onerous for
diagnosis of CD of the terminal ileum44–46 when compared patients and may result in additional radiation exposure, but
with small bowel radiology, whether performed as follow the inherent problem of non-intubation strategies is a
through (SBFT), intubation (small bowel enema (SBE), diminished ability to ensure even distension of the small
enteroclysis), or meal with pneumocolon (SBMP). bowel for accurate assessment of strictures. However,
Enteroscopy with biopsy by a push endoscope is safe and strictures may only be detectable by opacification with
useful procedure for diagnosis of CD in selected patients with distension. Therefore, SBE has been considered the optimum
suggestive symptoms after failure of conventional radiology.47 investigation for CD, with a sensitivity of 93% and a
The accuracy of capsule enteroscopy remains to be defined specificity of 92% to exclude small bowel disease.51–53 In
(below). routine practice SBFT is simpler and may be preferred; it was
A plain abdominal radiograph is valuable in the initial superior to SBE for detecting mucosal disease, fistulas, or
assessment of patients with suspected severe CD by providing gastroduodenal involvement in a comparative study in
evidence of small bowel or colonic dilatation, calcified calculi, CD,54 55 but is operator dependent and not as good for
sacroiliitis, or the impression of a mass in the right iliac fossa. strictures. The debate is unlikely to be resolved by wireless
It is not a diagnostic test for CD. capsule enteroscopy or other techniques in the near future.
US is not good at identifying the extent of CD, but its non-
2.3 Extent of disease ionising character make it suitable for the initial evaluation
2.3.1 Procedures recommended for establishing the of a young population, especially for ileal CD. The sensitivity
extent of CD for US is 87%–95% when performed by specialists, which is
somewhat less than barium studies,56–60 but is even more
ECCO statement 2G operator dependent. It misses lesions predominantly in the
upper GI tract or rectosigmoid. The role of colour, power
In a patient with evidence of CD determined by ileocolono- Doppler and contrast enhanced power Doppler investigation
scopy, further investigations are recommended to examine of the bowel wall for defining disease activity remains to be
the location and extent of CD in the small bowel irrespective determined.
of the endoscopic and histological findings in the terminal Intestinal imaging with helical CT-enteroclysis or CT-
ileum [EL1b, RG A] enterography has improved appreciably, leading to reports
that it is complementary or even superior to barium studies
CD may affect the ileum out of reach of an endoscope, or for the detection of involved segments.61 62 MRI has also
involve more proximal small bowel (10% of patients.) undergone technical developments that may yet make it the

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i6 ECCO consensus on Crohn’s disease

method of choice complementary to ileocolonoscopy and determine the full significance of any narrowing even with
biopsy for assessing location, extent, and disease activity. Its intubation studies. Reflux of gas or smooth muscle relaxants
ability to detect extramural complications (abscess, fistula, can distend narrowed loops. Enteroclysis most reliably

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sacroiliitis, gall stones, renal calculi) is an added advantage. differentiates irreversible stenosis from functional spasm.
However, magnetic resonance enteroclysis (MRE) is currently US is helpful in detecting pre-stenotic dilatation in small
more invasive than SBE, as it involves intravenous, oral and bowel strictures in severe cases that are candidates for
rectal contrast, as well as intravenous antiperistaltic agents. surgery.71
Superior sensitivity and specificity by MRE (95% and 93%) If colonoscopy is incomplete because of stricture, then
compared with SBE (85% and 77%) has been claimed for the double, or even single contrast barium enema are usually
primary diagnosis of CD.63 MRE can provide useful informa- procedures of first choice.72 CT colonography (CTC) can show
tion about the activity of disease.64 65 the mucosal pattern and show colitis proximal to a stricture,
Leucocyte scintigraphy is safe, non-invasive, and poten- but may not identify all strictures seen on colonoscopy.73–75
tially permits assessment of the presence, extent, and activity Differentiation between inflammatory and fibrostenotic
of inflammation patients who are not taking corticosteroids, strictures is crucial to the choice of therapy, but current
but it lacks specificity.66 techniques are insufficiently accurate. Disease activity at a
It is premature to recommend any single procedure for stricture is inferred from by the presence or absence of
imaging of the small bowel. However, the very variety of ulceration that indicates active inflammation. Contrast
techniques make it most desirable that clinicians discuss enhanced Doppler US may be valuable in determining
imaging with an appropriate radiologist, so that results can disease activity within strictures.76–78 Both CT and MRI
be reviewed in the context of the clinical history.2 67 illustrate mural changes with disease activity, but MRI is
more sensitive.65 79 80
2.3.2 Procedures recommended for establishing the
extent of stricturing CD 2.3.3 Procedures recommended for detecting
extramural complications

ECCO statement 2I
ECCO statement 2K
Intestinal stenosis is defined by symptoms of obstruction,
When an extramural complication is suspected, including
bowel lumen narrowing, and/or pre-stenotic dilatation. The
fistula or abscess, US, CT, and/or MRI are appropriate
significance of the extent of luminal narrowing is not clearly
investigations [EL1c, RG A]
defined [EL5, RG D]

US is an operator dependent, but readily available, diagnostic

The procedures above (section 2.3.1) apply to stricturing tool for the diagnosis of extramural complications in CD. For
disease, but obstructive symptoms create their own the detection of fistulas and abscesses, respective sensitivities
challenge. The most reliable criterion for defining a stricture of 87% and 100% have been reported.81
is a localised, comparatively short persistent narrowing, CT and MRI are highly accurate in complicated CD,
whose functional effects may be judged from pre-stenotic especially for the detection of fistulas, abscesses, and
dilatation.68 phlegmons.82 83 The important advantages of MRI compared
with CT include superior tissue contrast, absence of radiation
exposure, capability of selecting cross sectional planes
ECCO statement 2J (transverse, coronal, sagittal), and higher sensitivity for
intestinal and extraintestinal changes in CD.79 Surgically
When endoscopic intubation of the intestine is not possible, compared sensitivities for the detection of fistulas and
radiological studies are necessary to determine disease abscesses of 83% and 100% respectively, have been reported
extent and location [EL1a, RG A]. Small bowel enema for for MRI.84 MRI enteroclysis is good and probably better than
small bowel disease and double contrast barium enema for US85 for detecting extramural complications of CD, but
large bowel disease are recommended [EL1c, RG A]. fluoroscopic studies are poor value.63 Laparoscopy may be
Complementary imaging procedures may be performed, necessary in selected patients, especially when the differ-
including US, CT, and/or MRI [EL1a, RG A]. Differentiation ential diagnosis of intestinal tuberculosis is being considered.
between inflammatory and fibrostenotic bowel stenosis
would be very helpful, but current techniques do not permit 2.3.4 Role of gastroduodenoscopy and biopsy in a
an accurate distinction patient with CD

ECCO statement 2L
Plain film radiography and CT have similar accuracy in
In routine practice gastroduodenoscopy is only recom-
identifying small bowel obstruction. Plain film radiography
mended in patients with upper gastrointestinal symptoms
remains the initial method, but the ability to depict the cause
[EL5, RG D]
of obstruction makes CT an important additional diagnostic
tool.69
When small bowel stenosis is suspected an enteroclysis
examination best distends the bowel to reveal extent and CD involving the upper gastrointestinal tract is almost
number of strictures. Based on availability, SBE is recom- invariably accompanied by small or large bowel involve-
mended as investigation of first choice, but MRI-enteroclysis ment.86–88 Gastric biopsies may be useful when a patient has
is comparable.70 The functional significance of a stricture is colitis unclassified, as focal active gastritis in the absence of
best illustrated by pre-stenotic dilatation, but it is difficult to ulceration may be a feature of CD (section 3.2.5).

[Link]
ECCO consensus on Crohn’s disease i7

2.3.5 Role of wireless capsule endoscopy (WCE) in management? and which features if any, can be used for
suspected or proven CD assessment of disease activity?

3.1 Procedures for the diagnosis with endoscopic

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biopsies
ECCO statement 2M
3.1.1 Number of biopsies
Wireless capsule endoscopy (WCE) represents an advance
for small bowel imaging, but large prospective studies are ECCO statement 3A
needed to confirm the diagnostic relevance in CD. WCE may
be considered in symptomatic patients with suspected small
For a reliable diagnosis of CD ‘‘multiple’’ biopsies from five
bowel CD in whom a stricture/stenosis has been excluded,
sites around the colon (including the rectum) and the ileum
endoscopy of terminal ileum is normal or not possible, in
should be obtained. Multiple biopsies implies a minimum of
whom fluoroscopic or cross sectional imaging have not
two samples from each site [EL2, RG B]
showed lesions [EL2, RG B]

WCE is a novel method of directly visualising small bowel

ECCO statement 3B
lesions in patients with IBD that may be missed by traditional
endoscopic or radiological procedures. Initial studies suggest
In patients with fulminant colitis, two samples from at least
that WCE is a superior and more sensitive procedure than
one site should be obtained [EL5, RG D]
SBFT and CT-enteroclysis in establishing the diagnosis and
estimating the extent of CD.89–92 However, CD associated
lesions seen at WCE still need more precise definition,
because specimens for histological evaluation are not For the initial diagnosis, analysis of a full colonoscopic biopsy
obtained. Large prospective studies are needed to position series, rather than a single rectal biopsy, produces the most
WCE in a diagnostic algorithm for CD. Contraindications for reliable diagnosis of CD.96–103 Samples are preferably obtained
WCE include gastrointestinal obstruction, strictures or both from areas that are involved by the disease and from
fistulas, pacemakers or other implanted electromedical uninvolved areas. During follow up examinations, a smaller
devices, and swallowing disorders.93 number of biopsy samples may be useful to confirm the
diagnosis. In post-surgical follow up, biopsies of the neo-
2.3.6 Procedures recommended preoperatively terminal ileum are indicated when disease recurrence is
suspected. Where patients have undergone ileal pouch-anal
anastomosis, biopsies of the afferent limb are indicated when
ECCO statement 2N
CD is suspected. Multiple biopsies are indicated when the
patient is investigated during screening for dysplasia ( =
Preoperative imaging should follow strategies used for the intraepithelial neoplasia).
primary diagnosis of CD [EL5, RG D]
3.1.2 Handling of biopsies

Small bowel mucosal lesions proximal to resection margins

are found in about 65% of patients at the time of surgical ECCO statement 3C
intervention, most often undetected by radiography. These
lesions do not, however, influence postoperative outcome.94 95
The biopsy samples should be accompanied by clinical
information including the age of the patient, duration of
3.0 THE HISTOLOGICAL DIAGNOSIS OF CD disease, and duration and type of treatment [EL5, RG D]
During the past 25 years, several elements have influenced
the accuracy of the histological diagnosis of CD. The
widespread introduction of colonoscopy permitted the
analysis of multiple mucosal biopsies from different segment
of the colon and the ileum. The introduction of new therapies ECCO statement 3D
inducing healing of the mucosa has made the pathologist
aware of the impact of treatment upon the diagnostic All tissue samples should be fixed immediately by immersion
features. in buffered formalin or an equivalent solution before
For this section articles reporting original research into the transport [EL5, RG D]
reproducibility, sensitivity, or specificity of individual fea-
tures for the histological diagnosis of CD were sought from
the literature using Medline and Pubmed. As further
selection criteria, only those features that achieved moderate ECCO statement 3E
reproducibility judged by k value, or findings that were
confirmed by subsequent studies, were considered. The As lesions may be mild or focal it is recommended that
purpose is to propose consensus guidelines for the histolo- multiple sections from each sample are examined [EL2, RG B]
gical diagnosis of CD. The aspects discussed include:
procedures required for a proper diagnosis; features that
can be used for the analysis of endoscopic biopsies; features
that can be used for the analysis of surgical samples; and Biopsies from different regions should be handled in a way
diagnostic criteria. Questions that are addressed include: how that the region of origin can be identified. This can be done
many features should be present for a firm diagnosis? is it by using different containers, multi-well cassettes,or an
useful to search for dysplasia? the role of histology in acetate strip. Orientation of the samples using filter paper

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i8 ECCO consensus on Crohn’s disease

(submucosal side down) before fixation, may yield better 3.2 Diagnostic features
results, because it permits a better assessment of architec- 3.2.1 Combined microscopic features
tural abnormalities [EL5, RG D]. The ideal number of

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sections to be examined in routine practice is not established,
but numbers vary between two and six in different ECCO statement 3F
studies.102 103 The diagnostic yield increases when more
sections are examined. It is not clear whether serial Focal (discontinuous) chronic (lymphocytes and plasma cells)
sections or step sections from different levels of the sample inflammation and patchy chronic inflammation, focal crypt
should be examined. In one comparative study of rectal irregularity (discontinuous crypt distortion), and granulomas
biopsies, serial sectioning increased the ability to detect focal (not related to crypt injury) are the generally accepted
abnormalities including granulomas compared with step microscopic features that permit a diagnosis of CD [EL2, RG
sectioning. Confirmation of this finding is needed.104 In B]. The same features and, in addition, an irregular villous
routine practice, step sections may be the simplest procedure. architecture, can be used for analysis of endoscopic biopsy
Obtaining two or three tissue levels has been proposed, each samples from the ileum. If the ileitis is in continuity with colitis,
consisting of five or more sections.105 Routine staining with the diagnostic value of this feature should be used with
haematoxylin and eosin are appropriate for diagnosis. [EL5, caution [EL2, RG B]
RG D] At present special stains, immunohistochemistry, or
other techniques for diagnostic purposes are not needed
routinely. A large variety of microscopic features have been identified
This proposal is in agreement with guidelines proposed by that help to establish a diagnosis of CD, and reported in the
the German, Austrian, and Swiss inflammatory bowel disease literature. They are summarised in table 3.1. The reproduci-
study groups and the British Society of Gastroenterology bility of these features, as well as the sensitivity and
initiative.100 106–110 The use of multiple biopsies from different specificity have been studied repeatedly (section 3.2.5).
sites is supported by the expert opinion of clinicians, except
for patients presenting with fulminant colitis. Fifty eight per 3.2.2 Focal or patchy inflammation
cent of the clinicians agree to take two samples from one or Focal or patchy chronic inflammation means a variable
two regions in fulminant colitis. Eight per cent do not increase in lamina propria cellularity across the biopsy
perform endoscopy in fulminant colitis and 34% would take specimen and not confined to the superficial zone. A focal
only one sample. The proposal to use multiple biopsies for the increase implies a normal background cellularity with a
diagnosis of CD is supported by data from the literature.96 97 localised increase in cells. Patchy increase means an
For fulminant colitis, there are no appropriate data available. abnormal background cellularity with variable intensity.

Table 3.1 Microscopic features used for the diagnosis of Crohn’s disease
Colon
Architecture
Crypt architectural irregularity: Focal
Diffuse
Reduced crypt numbers/mucosal atrophy
Irregular surface
Chronic inflammation
Distribution I Focal increase in intensity
Patchy increase
Diffuse increase
Distribution II Superficial
Transmucosal
Basal plasma cells
Granulomas
Mucin granulomas
Polymorph inflammation
Lamina propria
Crypt epithelial polymorphs
Focal
Diffuse
Crypt abscess
Polymorph exudates
Epithelial changes
Erosion/ulceration
Mucin Depletion
Preservation
Paneth cells distal to hepatic flexure
Epithelial associated changes
Increased intraepithelial lymphocytes .15
Terminal ileum
Architecture
Villus irregularity
Crypt architecture irregularity
Epithelial changes
Pseudopyloric gland metaplasia (ulcer associated cell lineage (UACL))
Comparison between different segments
Distribution of inflammation along the colon: gradient from proximal
to distal
Ratio of number of biopsies with focal cell infiltration to number of
biopsies with mononuclear cell infiltration

[Link]
ECCO consensus on Crohn’s disease i9

Focal or patchy increase should not be confused with the inflammation (focal) or, preferably, architectural abnormal-
presence of normal lymphoid aggregates. Differences in ities. A pseudovillous appearance of the colorectal surface is
cellularity between multiple biopsy specimens can be more predictive of ulcerative colitis, while focal architectural
assessed with greater reproducibility than variation within abnormalities favour CD. However, finding a granuloma is not

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a single specimen. always necessary for a diagnosis of CD. Additional features
that have been found to be useful are increased intraepithelial
3.2.3 Crypt irregularity lymphocytes,96 transmucosal inflammation,112 focal chronic
Crypt irregularity implies crypt abnormalities in .10% of the inflammation without crypt atrophy, focal cryptitis (although
crypts when focal or patchy inflammation are present. Crypt reproducibility is poor),100 120 aphthoid ulcers, disproportionate
irregularity can be either crypt distortion (non-parallel crypts, submucosal inflammation, nerve fibre hyperplasia,121 and
variable diameter, or cystically dilated crypts), crypt branch- proximal location of ulceration and architectural distortion.
ing, and crypt shortening.100 The presence of more than two When multiple biopsies are available, ileal involvement and a
branched crypts in a well orientated biopsy specimen can be distribution of the inflammation showing a proximal to distal
regarded as abnormal.100 gradient can also be useful. The absence of features that are
highly suggestive or diagnostic of ulcerative colitis, such as
3.2.4 Granulomas diffuse crypt irregularity; reduced crypt numbers and general
The granuloma in CD is defined as a collection of epithelioid crypt epithelial polymorphs, can also orient towards a
histiocytes (monocyte/macrophage cells), the outlines of diagnosis of CD.
which are often vaguely defined. Multinucleated giant cells In difficult cases, gastric biopsies might help establish the
are not characteristic and necrosis is usually not apparent. diagnosis of CD by the presence of granulomas or focally
Only granulomas in the lamina propria not associated with enhanced or focal active gastritis. The latter is characterised
active crypt injury may be regarded as a corroborating feature by the absence of Helicobacter pylori and the presence of a
of CD. Granulomas associated with crypt injury are less perifoveolar or periglandular cellular infiltrate composed of
reliable features.111 Non-caseating granulomas, small collec- mononuclear cells (CD3+ T cells and CD68+ cells) and
tions of epithelioid histiocytes, and giant cells, or isolated granulocytes. Focal gastritis is not exclusive to CD [EL4, RG
giant cells can be seen in infectious colitis (granulomas C].122–126
suggest Mycobacteriumsp, Chlamydiasp, Yersinia pseudotuberculo-
sis, Treponema sp; microgranulomas suggest Salmonellasp, 3.3 Histology and dysplasia-intraepithelial neoplasia
Campylobactersp, Yersinia enterocolitica; giant cells suggest 3.3.1 Number of biopsies
Chlamydia sp) and must not be regarded as evidence for CD.

3.2.5 Number of features needed for diagnosis ECCO statement 3G

The selection of these features is based upon a systematic
literature review. They achieve a diagnostic sensitivity and The microscopic features for the diagnosis and grading of
specificity of at least 50% and a moderate to good dysplasia-intraepithelial neoplasia of the colon in Crohn’s
reproducibility (k of 0.4 or percentage agreement of at least disease are the same as those proposed for ulcerative colitis
80%).103 104 112 113 They were presented to a panel of experts and, similarly, a second opinion is recommended for a firm
and scored according to the quality of the study and expert diagnosis [EL2, RG B]
opinion. Focal crypt irregularity scored highest on the
evidence of more than one valid study of adequate size and
from expert opinion; focal or patchy chronic inflammation
was validated by evidence from single paper and expert
opinion. The features were also tested in a workshop,
ECCO statement 3H
involving non-expert and expert pathologists and selected
by 50% or more of the pathologists correctly identifying each As for ulcerative colitis, sporadic adenomas may be difficult
case.96 The patchy nature of the inflammation is only to distinguish from dysplasia associated lesions or masses.
diagnostic in untreated adult patients. Inflammation can The distinction is however important, because the manage-
become patchy in UC under treatment, and young children ment of sporadic adenomas differs from that of colitis
(age ,10 years) with UC may present with discontinuous associated dysplasia. The patient’s age, the site, and
inflammation.114–119 morphology of the lesion, along with biopsies of flat
The presence of one single feature is not regarded as surrounding mucosal, may be helpful in this distinction
sufficient for a firm diagnosis. For single or multiple [EL2, RG B]
endoscopic samples there are no data available as to how
many features must be present for a firm diagnosis of CD. For
surgical material, it has been suggested that a diagnosis of Patients with extensive Crohn’s colitis carry an increased risk
CCD should be made when three features are present in the of colorectal cancer. Endoscopy with biopsy can be used for
absence of granulomas, or when an epithelioid granuloma is secondary prevention and the detection of dysplasia (intra-
present with one other feature provided that specific infections epithelial neoplasia) in UC [EL2, RG C]. The optimal number
are excluded [EL5, RG D].109 The same definition could be of biopsies required for a reliable diagnosis of intraepithelial
proposed for mucosal samples obtained during endoscopy. The neoplasia has not been established. It has been proposed that
following features can be identified in the mucosa and thus in 6 to 10 samples from different sites in the colon should be
endoscopic biopsy samples: granulomas and focal (segmental obtained, as suggested for UC. The current recommendation
or discontinuous) crypt architectural abnormalities, in con- is to biopsy the colon at 10 cm intervals. Biopsies are labelled
junction with focal or patchy chronic inflammation (chronic is separately so that the segment of colon from which the tissue
defined as presence of lymphocytes and plasma cells), or is obtained can be subsequently identified. It has been
mucin preservation at active sites. These are, therefore, estimated that 33 biopsy specimens are required to give 90%
potentially reliable markers for the diagnosis of CD. confidence in the detection of dysplasia if it is indeed
Most expert clinicians (91%) and all pathologists agree that present.127 These studies on UC have not been replicated in
the presence of a granuloma and at least one other feature Crohn’s colitis. The focal nature of inflammation in Crohn’s
establishes a diagnosis of CD. The second feature can be either colitis, the possibility of strictures and prevalence of

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i10 ECCO consensus on Crohn’s disease

segmental resection means that surveillance practice in UC summarised in boxes 3.2 and 3.3. Fat wrapping has a high
cannot be transferred directly to Crohn’s colitis. The purpose predictive value for the diagnosis of CD.131 132
of this section is not designed to make surveillance
recommendations, but to acknowledge that if it is performed

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then the number of biopsies necessary to detect dysplasia is Box 3.2 Macroscopic features for the diagnosis
large. The use of targeted biopsies, aimed at lesions identified of Crohn’s disease
by chromoendoscopy or endomicroscopy, may change the
policy of taking biopsies in the future. N Ileal disease*
3.3.2 Microscopic features N Rectum typically spared
Microscopic features that are used for a diagnosis of N Confluent deep linear ulcers, aphthoid ulcers
intraepithelial neoplasia include architectural and cytological N Deep fissures
abnormalities. Architectural abnormalities are crowding of N Fistulas
glands, thickening of the mucosa, lengthening and distortion N Fat wrapping*
of the crypts with excessive budding, and increased size.
Surface and crypts are lined by tall, high columnar cells in N Skip lesions (segmental disease)
which there is some mucus differentiation. Mucin tends to be N Cobblestoning
in columnar cells rather than in the usual goblet cells. N Thickening of the intestinal wall*
Nuclear changes are morphologically similar to those seen in
tubular adenomas: hyperchromatic and enlarged nuclei, with
N Strictures

nuclear crowding and frequent overlapping. The nuclei are *Typical discriminating features for a diagnosis of Crohn’s
also typically stratified. Mitotic figures may be present in the disease compared with other conditions
upper part of the crypt, and even in the surface (which is
abnormal).128 129

3.3.3 Additional techniques Box 3.3 Microscopic features for the diagnosis of
The use of additional techniques (including flow cytometry, Crohn’s disease in surgical specimens
immunohistochemistry) and the search for markers (such as
the expression of p53) can be helpful for solving diagnostic
problems and to support the diagnosis of intraepithelial N Transmural inflammation*
neoplasia. These techniques, however, identify changes that N Aggregated inflammatory pattern, transmural lym-
are not entirely the same as dysplastic changes, which phoid hyperplasia*
represent a complex phenomenon. Therefore, and because of
practical availability and costs, the simple morphological
N Submucosal thickening (expansion by fibrosis—fibro-
muscular obliteration and inflammation)
recognition of dysplasia remains important for the manage-
ment of the cancer risk in CD.
N Fissures
N Sarcoid granuloma (including in lymph nodes)*
3.4 Surgery and pathology N Abnormalities of the enteric nervous system (submuco-
sal nerve fibre hyperplasia and ganglionitis)*

ECCO statement 3I
N Relatively unchanged epithelia—mucin preservation
(goblet cells often normal)
A surgical sample needs a complete macroscopical exam- *Typical discriminating features for a diagnosis of Crohn’s
ination, carried out in an orderly and systematic manner, disease compared with other conditions
including photographic documentation, preferably at the
time when the specimen is removed [EL5, RG D]. Once
macroscopical observations are completed, the sample is
opened along its longitudinal axis (along the antimesenteric 3.5 Histology and disease activity
or antimesocolic border, except perhaps at the sites of any
carcinoma, where it may be preferable to leave that small
segment unopened during fixation) and specimens for ECCO statement 3K
microscopy are collected, including the lymph nodes,
terminal ileum, and appendix [EL2, RG B] The pathology report should give an indication of the activity
of the disease. Inactivity in the biopsy may not reflect
inactivity in the patient [EL5, RG D]

ECCO statement 3J

The optimum number of samples from a colectomy specimen Histological examination is routinely used for the diagnosis
that should be obtained has not been established. However, of UC and CD. The occurrence of healing of mucosal
multiple samples will improve the diagnostic yield. It is a inflammation has already been noted as a feature of
mistake to sample only visible lesions. The samples can be resolution in UC. Therefore, biopsies are used to discriminate
processed routinely [EL5, RG D] between quiescent disease, inactive disease, and different
grades of activity in UC. This has led to the introduction of
scoring systems for the assessment of disease activity in UC
and their use in clinical drug trials.127
When surgical samples are available, the macroscopic aspects In contrast with UC, disease activity is not generally
of the condition and the transmural character of the assessed by pathologists for CD. This is mainly attributable to
disease can be identified and in general many more features the discontinuous character of the disease, inducing sam-
can be used for diagnostic purposes.121 130 The features are pling error, and the fact that the ileum may be the only area

[Link]
ECCO consensus on Crohn’s disease i11

involved. Sampling error is very important, especially when constellation. In this capacity, genetic tests may be gene
only rectal biopsies are available. Microscopic analysis of based, but may also comprise protein based tests of gene
multiple samples from different segments of the colon and function. Other tests designed to discriminate or classify CD

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ileum might provide useful information and permit assess- include serological tests.
ment of disease activity. Arguments in favour come from NOD2/CARD15 mutations have been clearly associated
other diseases such as UC and H pylori related gastritis and with susceptibility to CD [EL1a].145–147 They were further
from clinical drug trials. In UC, basal plasmacytosis can also related to particular phenotypes (characterised by ileal and
help to predict relapse, while adequate control of the stricturing disease) [EL1a].148–153 The relative importance of
inflammation seems important for the prevention of the NOD2 mutations differs between white populations and non-
development of cancer,131–136 but neither have yet been white populations (mostly no NOD2 mutations) but also
studied in CD. The data available on histology and activity within Europe. It is expected that further disease suscept-
for CD are limited. Several clinical drug trials have shown ibility genes will be detected soon [EL2b].154 155 Genetic tests
that medical treatment can change the mucosal histology, are not yet implemented in clinical routine strategies because
promoting healing and normalisation of the mucosa.135–143 of low individual predictive value and because no preventive
There is, however, no general agreement among expert or therapeutic strategies based on the genetic findings exist to
clinicians about the use of microscopy to assess disease influence disease. Counselling should be done before any
activity. If biopsies are used, then multiple samples have to be genetic test. Counselling should be performed using an
obtained and analysed. The presence of epithelial damage in interdisciplinary approach, including human genetics and
association with neutrophils is a marker of disease activity.133 disease specialists.
In CD a multivariate logistic regression model showed that Serological tests (ASCA/ANCA) have a high specificity for
severe lymphocytic (and eosinophilic) infiltration of the the diagnosis of CD if the pattern is positive (ASCA+/ANCA-)
lamina propria, presence of crypt atrophy and absence of [EL2a]. The predictive value is too low for routine clinical use
lymphocytic infiltration of the epithelium are the best [EL2a].156–161 Clinical permeability scores using inert macro-
variables for predicting uncomplicated disease.144 molecules (such as lactulose, L-rhamnose, or mannitol) show
abnormal values in a fraction of patients. They have some
predictive value for relapse, but they are not available outside
4.0 CLASSIFICATION OF CROHN’S DISEASE of specialised centres and are of no predictive value for
Disease classification is an important step to provide individual patients [EL2a].162 163
appropriate tools that enable us to dissect differences in the
features and behaviour of CD. Several ways of classifying CD
4.2.2 Classification by phenotype
have been used in the past. CD has been classified by disease
The Vienna classification was introduced at the World
phenotype (Rome or Vienna classification, modified in
Congresses of Gastroenterology in 1998 and provides the
Montreal), by disease activity (mostly according to the
most recent international consensus on CD phenotype.68 Age
CDAI), and by response to therapy (mainly corticosteroids:
at diagnosis (A), disease location (L), and disease behaviour
‘‘corticosteroid resistant’’ or ‘‘corticosteroid dependent’’,
(B) are the three categories for allocating patients. The A and
above). Some disease causing mutations have been identified
L category seem to be stable during the course of disease, but
in the recent past, classification by genetic markers may be
the B category is not.164 Patient classification by phenotype
appropriate. Also immunological features such as ASCA or
has an impact on the choice of medication with regard to
ANCA may look attractive for classifying the disease disease location and disease behaviour (see also section on
(immunotyping). The best classification of course would be therapy). The Vienna Classification is a first step towards
by cause of disease, which is, however, still obscure. standardising this process. At the World Congress of
Gastroenterology in Montreal (2005) an update of the
4.1 General recommendations Vienna classification was proposed,165 which includes upper
gastrointestinal and perianal modifiers for disease location
ECCO statement 4A and behaviour. The possibility of including genetic and
serological markers in the classification was examined and
No evidence based recommendation can be made to the clinical reclassification is in the process of being
implement the routine clinical use of: genetic tests (for validated.
example, NOD2/CARD15, OCTN1 and 2, DLG5 or
combinations); stool markers (for example, calprotectin, 4.2.3 Classification by CRP or other indicators of
lactoferrin); serological markers (for example, ASCA, inflammation
ANCA, ompC, I2, flagellin antibodies); intestinal perme- Clinical disease activity is habitually determined by CDAI and
ability testing; or phenotype driven classifications separates patients with active disease from patients with
quiescent disease. The CDAI is heavily weighted towards
subjective symptom reports such as diarrhoea, abdominal
pain, or general wellbeing. It does not necessarily reflect the
ECCO statement 4B
inflammatory activity in the gut. Inflammation related
markers are therefore detected from the serum or the stool.
Serum levels of CRP are useful for assessing a patient’s risk of
Therefore more reliable parameters including laboratory tests
relapse [EL2b, RG B]. High CRP levels are indicative of active
of inflammation would be useful.
disease [EL2a, RG B] or a bacterial complication [EL3, RG C].
Raised serum CRP is found in patients with endoscopically
CRP levels can be used to guide therapy and follow up [EL2a,
active CD and low levels of CRP identify patients in stable
RG B]
remission. The CRP in remission may help identify those at a
higher risk of relapse [EL2b] (see also section 6.1.2). When
101 patients with CD were followed up prospectively for two
4.2 Specific components years, half had a raised CRP that correlated well with clinical
4.2.1 Classification by genetic or other markers activity. About a third presented with active disease despite a
Genetic tests are considered to represent any diagnostic test normal CRP and a third had a raised CRP but clinically
that permits the determination of a particular genetic inactive disease. The likelihood of relapse after two years was

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i12 ECCO consensus on Crohn’s disease

higher for the patients with an increased CRP compared with W Reinisch, Univ-Klinik Innere Medizin IV, Abt Gastroenterology and
those with a normal CRP.166 The GETAID group also Hepatology, Vienna, Austria
prospectively followed up 71 CD patients with medically Competing interests: the authors have variously received unrestricted
educational grants, consultancy fees and/or hospitality from all

Gut: first published as 10.1136/gut.2005.081950a on 15 February 2006. Downloaded from [Link] on May 25, 2023 by guest. Protected by copyright.
induced remission and measured laboratory markers (full
blood count, CRP, ESR, a1 antitrypsin, orosomucoid) every pharmaceutical companies in the field of inflammatory bowel disease,
six weeks.161 In total, 38 patients relapsed (defined as a but no author was paid for this work nor did any company contribute to
the consensus statements or text.
CDAI.150 with an increase of .100 points from baseline)
after a median of 31 weeks. Only two laboratory markers
were predictive of relapse: CRP (.20 mg/l) and ESR
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