Diagnostic Delay in Adult Inflammatory Bowel Disease: A Systematic Review

doi:10.21203/rs.3.rs-1753316/v1

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Diagnostic Delay in Adult Inflammatory Bowel Disease: A Systematic Review

https://doi.org/10.21203/rs.3.rs-1753316/v1

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Background

The extent of diagnostic delay in inflammatory bowel disease (IBD) is incompletely understood. We aimed to understand the extent of diagnostic delay of IBD in adults and identify associations between patient or healthcare characteristics and length of delay.

Methods

Articles were sourced from EMBASE, Medline and CINAHL from inception to April 2021. Inclusion criteria were adult cohorts (18 ≥ years old) reporting median time-periods between onset of symptoms for Crohn’s disease (CD), ulcerative colitis (UC) or IBD (i.e., CD and UC together) and a final diagnosis (diagnostic delay). Narrative synthesis was used to examine the extent of diagnostic delay and characteristics associated with delay. Sensitivity analysis was applied by the removal of outliers.

Results

Thirty-one articles reporting median diagnostic delay for IBD, CD or UC were included. After sensitivity analysis, the majority of IBD studies (7 of 8) reported a median delay of between 2-5.3 months. From the studies examining median delay in UC, three quarters (11 of 16) reported a delay between 2–6 months. In contrast, three quarters of the studies (17 of 23) including CD samples, reported a delay of between 2–12 months. No characteristic had been examined enough to understand their role in diagnostic delay in these populations.

Conclusions

This systematic review provides robust insight into the extent of diagnostic delay in IBD, particularly in CD, and suggests further intervention is needed to reduce delay. Furthermore, our findings provide a benchmark value range, which such future work can be measured against.

Diagnostic Delay

Inflammatory Bowel Disease

Crohn’s Disease

Ulcerative Colitis

Inflammatory bowel disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract, the most prevalent examples being Crohn’s disease (CD) and ulcerative colitis (UC)[1]. Approximately 6.8 million cases of IBD were reported globally in 2017, with nearly a quarter of these cases in North America, resulting in a significant personal and societal burden [2].

The clinical presentation of IBD is pleomorphic, but can include change in bowel habit, rectal bleeding, fatigue and weight loss [3]. In addition, approximately 25–40% of individuals with IBD display extra-intestinal manifestations, which include arthritis, axial spondyloarthritis, uveitis, erythema nodosum and primary sclerosing cholangitis [4]. The range of such presenting symptoms can make it challenging for clinicians to promptly identify patients with IBD, and symptoms can be attributed to other conditions such as irritable bowel syndrome, all of which can lead to diagnostic delay [5]. Such delays may be further contributed to by factors such as patient demographics, geographical location and the presence of extra-intestinal manifestations [6–9]. For example, in affected countries, symptoms of IBD may be mistaken for abdominal tuberculosis[10]. In cases of diagnostic delay, adverse impacts on clinical outcomes can occur, including an increased need for subsequent surgical intervention and poor response to medical therapy [11, 12].

Recent reports suggest the diagnostic delay of IBD can range anywhere from 5.3 months to 3.6 years [7, 13] and that delays in the diagnosis of CD are longer than for UC [6, 12, 14]. This wide variation reported in the differences in the delay experienced by patients, means the true extent of the problem of delay remains unclear. The aim of this systematic review was to provide a clearer benchmark range for the extent of diagnostic delay, as well as providing information on any characteristics that may be associated with delay.

Data Sources and Searches:

We conducted a systematic review by searching the medical literature databases of Medline, EMBASE and CINAHL from their inception to April 2021, using a combination of free-text and medical subject headings (MeSH) terms, or equivalents from each database (Supplementary Table 1). Search terms were devised for IBD and diagnostic delay using existing systematic reviews that explored other aspects of IBD, and reviews investigating diagnostic delay in other long-term conditions[15–17]. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed during the completion of this systematic review and the protocol was logged with PROSPERO (Registration number: CRD42018108886).

Study Selection:

The inclusion criteria were developed using the PICOS framework [18]. The included population were adults aged 18 years or older with a confirmed diagnosis of IBD, CD or UC. Studies with adult populations which included a proportion of participants under 18 years old were retained if the mean age implied the population was largely formed from participants above 18 years old. Studies also had to include the primary outcome of interest, a reported average time-period of diagnostic delay for IBD, CD or UC from symptom onset to final diagnosis.

Studies were excluded if their design included case studies or case series with less than ten participants, literature reviews, systematic reviews or conference abstracts. There were no restrictions on time of publication, as databases were searched from inception. Articles in languages other than English were included, individuals who spoke the language were then requested to make initial assessments and then, if necessary, quality appraise and extract pertinent data, with Google Translate also being used if necessary.

Once the database searches had been undertaken using the reported criteria, the reference manager software Mendeley was used to remove duplicates (Version 1.16.1, Mendeley Ltd., London, UK). Authors EC and JAP then completed an independent title and abstract review of 50% of the initially identified articles each. Articles that progressed to abstract review underwent a second review, where EC reviewed the abstracts initially reviewed by JAP, and vice versa. These included abstracts then underwent a full text review, with EC independently reviewing all full texts and the remaining three authors (JAP, BS, ADF) reviewing a proportion of full texts each. Throughout the review process, disagreements between reviewers were resolved through discussion and by consulting an arbitrating author (BS).

Data Extraction and analysis:

Data extraction of included articles was completed by two reviewers (EC, JAP). The primary outcome of interest extracted was the reported average time-period of diagnostic delay of IBD (for articles that did not distinguish between CD and UC), CD or UC, from symptom onset to diagnosis. Average data regarding diagnostic delay was reported as mean or median values, with both being recorded along with their accompanying estimate of accuracy (standard deviation or interquartile range respectively). However, due to the typical non-normality of mean diagnostic delay data, only median values were used in this analysis [19]. The unit of time that articles used to report diagnostic delay varied from days to years, therefore delay data were converted into months to allow comparability of the data.

Additional data extracted included lead author, year of publication, time-period of participant recruitment, gender, country and mean sample age. Finally, information (where reported) on any specific characteristics (e.g., demographics, symptoms) and their association with reported diagnostic delay were identified in the articles and extracted. Regarding this characteristic data, no restriction was placed on the measure of central tendency here, but rather the focus was on whether differences in delay were experienced across comparator samples (i.e., extent of diagnostic delay in males vs females). The data from the included articles were examined using narrative synthesis. In the instance of outlier data, sensitivity analysis was performed, resulting in the exclusion of related studies.

Quality Appraisal:

A modified Newcastle-Ottawa Score (NOS) was used for quality appraising the included articles, carried out by EC and JAP. The NOS for cohort studies, and an adapted version of the NOS for cross-sectional studies were used [20]. The ‘Selection of participants’ and ‘Measurement of outcome’ were the two criteria of the NOS used to assess quality of articles. The representativeness of studies was assessed based on the geographical spread of recruitment, as well as variation in population characteristics.

Search results

10,119 unique articles were identified from the three selected databases and underwent title review. Following the exclusion of 6746 articles based upon title, 3373 articles underwent abstract review. From these, 429 articles were reviewed in full, leaving a final 31 articles that reported median data to be included for narrative synthesis. See PRISMA flowchart, below (Fig. 1).

Study characteristics

Of the 31 articles included in the review, 23 were cohort studies, of which 12 were retrospective [6, 12–14, 21–28], eight were prospective cohorts [9, 29–35] and three combined both methods [36–38]. Eight articles used a cross-sectional study design [5, 7, 8, 11, 39–42]. Nineteen studies were conducted in Europe, seven in Asia, four in North America and one in South America. Twenty articles were based in primary or secondary care, four in tertiary care and five from population registries. Two articles did not report the source from which the sample was drawn.

The majority of articles documented the criteria used to diagnose participants, typically using a combination of clinical features, radiologic and histologic findings to diagnose IBD. Formal diagnostic criteria used by articles included Lennard-Jones, ECCO and Copenhagen diagnostic criteria. Nine articles did not outline the use of any diagnostic criteria. The characteristics of each study included in the review have been summarised in Table 1.

Table 1

The characteristics of the studies included in the systematic review (n = 31)
Author, Year	Country	Study Design	Recruitment Period	Healthcare Setting	Condition	Diagnostic Criteria for IBD
Kyle, 1971[39]	Scotland	Cross-sectional	1955–1969	Not reported	CD	History and examination findings, radiology/endoscopy
Lind,1985 [29]	Norway	Prospective cohort	1975–1979	Secondary	CD	Standardised investigational program (colonoscopy/gastroscopy. biopsy, barium enema)
Foxworthy, 1985 [30] *	USA	Prospective cohort	1975–1983	Secondary	CD	Clinical presentation/course, radiologic/histologic/laparotomy appearance
Harper, 1986 [8] *	USA	Cross-sectional	1983–1984	Secondary	CD	Typical symptoms/findings, radiologic/endoscopic/operative features
Langholz, 1991 [31]	Denmark	Prospective cohort	1962–1987	Secondary	UC	Copenhagen criteria
Munkholm, 1992 [32]	Denmark	Prospective cohort	1962–1987	Secondary	CD	Copenhagen criteria
Timmer, 1999 [33]	Germany	Prospective cohort	1991–1995	Secondary	CD	Case definition criteria for definite or probable CD
Yang, 2000 [36]	South Korea	Retrospective & prospective cohort	1986 − 1977	Secondary	UC	Clinical, sigmoidoscopy, histological/cytological, radiologic/endoscopic features
Burgmann, 2006 [5]	Canada	Cross-sectional	2004–2005	Manitoba IBD registry	CD	ICD codes
Burgmann, 2006 [5]	Canada	Cross-sectional	2004–2005	Manitoba IBD registry	UC	ICD codes
Albert, 2008 [40]	Germany	Cross-sectional	2005–2007	Patient organization	CD	Not reported
Romberg-Camps, 2009 [34]	Netherlands	Prospective cohort	1991–2002	Population registry	CD	Lennard-Jones criteria
Romberg-Camps, 2009 [34]	Netherlands	Prospective cohort	1991–2002	Population registry	UC	Continuous mucosal inflammation without granuloma, affecting rectum +/ some/ all of the colon in continuity with rectum
Guariso, 2010 [37]	Italy	Retrospective & prospective cohort	1994–2008	Tertiary	IBD	Clinical, radiological, endoscopic + histologic findings
					CD	Clinical, radiological, endoscopic + histologic findings
					UC	Clinical, radiological, endoscopic + histologic findings
Vavricka, 2012 [6]	Switzerland	Retrospective cohort	2006–2009	Population registry	CD	Not reported
Vavricka, 2012 [6]	Switzerland	Retrospective cohort	2006–2009	Population registry	UC	Not reported
Burisch, 2014 [9]*	Europe	Prospective cohort	Jan 2010-Dec 2010	Secondary	CD	Copenhagen diagnostic criteria
Burisch, 2014 [9]*	Europe	Prospective cohort	Jan 2010-Dec 2010	Secondary	UC	Copenhagen diagnostic criteria
Pellino, 2015 [11]	Italy	Cross-sectional	2000–2009	Secondary	CD	Accepted ECCO criteria
Li, 2015 [23]	China	Retrospective cohort	2010–2014	Secondary	CD	Colonoscopy, enteroscopy, capsule endoscopy, histopathology, haematology
Maconi, 2015 [22]	Italy	Retrospective cohort	2012–2013	Primary and secondary	CD	Not reported
Basaranoglu, 2015 [24]	Turkey	Retrospective cohort	1995–2007	Tertiary	CD	clinical, radioscopic, endoscopic, histologic findings
Basaranoglu, 2015 [24]	Turkey	Retrospective cohort	1995–2007	Tertiary	UC	not reported
Lin, 2016 [25]*	Taiwan	Retrospective cohort	1991–2014	Not reported	UC	Not reported
Lee, 2017 [12]	South Korea	Retrospective cohort	2000–2015	Secondary	CD	Not reported
Lee, 2017 [12]	South Korea	Retrospective cohort	2000–2015	Secondary		Not reported
Cantoro, 2017 [21]	Italy	Retrospective cohort	1955–2014	Secondary	IBD	Not reported
Nguyen, 2017 [14]	USA	Retrospective cohort	2008–2015	Tertiary	CD	Not reported
Nguyen, 2017 [14]	USA	Retrospective cohort	2008–2015	Tertiary	UC	Not reported
Nahon, 2018 [38]	France	Retrospective & prospective cohort	2002–2015	Secondary	CD	Colonoscopy or radiologic examination which strongly suggested IBD
Nahon, 2018 [38]	France	Retrospective & prospective cohort	2002–2015	Secondary	UC
Irving, 2018 [41]	Finland, Italy, France, Canada, Germany, UK, Spain and Sweden	Cross-sectional	2013–2014	General population	CD	Not reported
Irving, 2018 [41]		Cross-sectional	2013–2014	General population	UC	Not reported
Szanto, 2018 [13]	Hungary	Retrospective cohort	2007–2015	Tertiary	CD	Lennard-Jones and accepted ECCO criteria
Szanto, 2018 [13]	Hungary	Retrospective cohort	2007–2015	Tertiary	UC	Lennard-Jones and accepted ECCO criteria
Banerjee, 2018 [26]	India	Retrospective cohort	Not reported	Secondary	CD	Not reported (paediatric CD = Porto criteria)
Kang, 2019 [27]	South Korea	Retrospective cohort	2006–2016	Secondary	UC	Clinical, radiological, endoscopic and pathologic findings
Novacek, 2019 [7]	Austria	Cross-sectional	2014–2015	Secondary	CD	ECCO criteria
Novacek, 2019 [7]	Austria	Cross-sectional	2014–2015	Secondary	UC	ECCO criteria
Walker, 2020 [28]	UK	Retrospective cohort		Primary and secondary	CD	ECCO-ESGAR criteria
Walker, 2020 [28]	UK	Retrospective cohort		Primary and secondary	UC	ECCO-ESGAR criteria
Gomes, 2021 [42]	Brazil	Cross-sectional	Not reported	Secondary	CD	Clinical, laboratory, endoscopic and histologic findings
Gomes, 2021 [42]	Brazil	Cross-sectional	Not reported	Secondary	UC	Clinical, laboratory, endoscopic and histologic findings
Chaparro, 2021 [35]	Spain	Prospective cohort	2017	Secondary	CD	ECCO criteria
Chaparro, 2021 [35]	Spain	Prospective cohort	2017	Secondary	UC	ECCO criteria
IBD- Inflammatory Bowel Disease; CD- Crohn’s Disease; UC- Ulcerative Colitis; ICD- International Classification of Diseases; ECCO- European Crohn’s and Colitis Organisation. *Studies providing diagnostic delay data for characteristic comparisons only

Quality appraisal

Of the 23 cohort studies, nine articles were deemed to be ‘truly representative’, 13 ‘somewhat representative’ and one sampled from a ‘selected group of users’. For the eight cross-sectional studies, three articles were ‘truly representative’, three ‘somewhat representative’, one sampled from a ‘selected group of users’ and one ‘did not report the sampling strategy’. Ascertainment of exposure (i.e., diagnosis of IBD) was determined by assessing ‘secure records’ in all cohort studies. For the eight cross-sectional studies, three studies used a ‘validated measurement tool’ to ascertain exposure, in three studies a ‘tool was available and described’ and two studies provided ‘no description’ of how participants with IBD were identified. Assessment of outcome, which in this systematic review was diagnostic delay, was done by ‘record linkage’ in 17 cohort studies and the remaining six by ‘self-report’. Two cross-sectional studies used ‘record linkage’, four used ‘self-reporting’ and two studies provided ‘no description’ for the assessment of outcome.

Extent of diagnostic delay

There were 11,597 participants providing median data related to IBD, with 4269 participants originating from studies that did not distinguish between CD or UC. 13,998 participants provided data related to CD and 12,895 provided data relating to UC. Median values of diagnostic delay of IBD were provided by nine articles and ranged from 2 to 96 months. Median delay of CD was provided by 24 articles, ranging from 2 to 84 months and 17 articles reported median delays of 2 to 114 months from initial symptoms to final diagnosis of UC (Table 2).

Table 2

Median diagnostic delay (months) for IBD, CD and UC, ordered from shortest to longest delay
Lead author	Year	Country	Sample Size (N)	% Male	Mean Age (SD)/[range]	Diagnostic Delay	IQR	Range
Inflammatory Bowel Disease (IBD)
Basaranoglu	2015	Turkey	282 CD- 98 UC- 184	64.2	40.1 (14.7)	2	0–18
Cantoro	2017	Italy	3392 CD- 1537 UC- 1855	53.1	Not reported	3	(0–13)
Romberg-Camps	2009	Netherlands	1187 CD- 476 UC- 630 IC- 81	48.9	CD- 34, [5–79] UC- 42, [8–84] IC- 42, [13–77]	3		0-480
Guariso	2010	Italy	179 CD-65 UC-99 IBD-U-15	-	29.1 [18–40]	3		0-135
Chaparro	2021	Spain	3611	52.8	42^† (30–55)	3		1–9
Szanto	2018	Hungary	911 CD- 428 UC- 483	46.3	Not reported	3.6	(0-9.6)
Novacek	2019	Austria	1265 CD- 830 UC- 435	49.4	40 (31–52)*, [18–87]	5.3	(2.3–16.4)
Gomes	2021	Brazil	658	44.6	44.2	13		5–38
Burgmann	2006	Canada	112 CD- 65 UC- 42 Proctitis- 3 IC-2	42.9	38 (12.9), [16–77]	96
Crohn’s Disease (CD)
Basaranoglu	2015	Turkey	98	52.0	37.8 (13.5), [17–79]	2	-	[0–18]
Guariso	2010	Italy	65	-	-	4	-	0–88
Timmer	1999	Germany	132	25	31 (23–47)*	5	-
Romberg-Camps	2009	Netherlands	476	39.3	34, [5–79]	5	-	[0-360]
Chaparro	2021	Spain	1647	50.2	41^† (28–54)	5	-	1–15
Nahon	2018	France	638			5	-	-
Kyle	1971	Scotland	175	38.3	Not reported	6	-	-
Lee	2017	South Korea	165	76.4	28.2 (13.8)	6.2	(1.5–21.5)	-
Novacek	2019	Austria	830	48.1	40 (31–52)*	6.4	(2.3–23.4)	-
Cantoro	2017	Italy	1537	53.1	Not Reported	7.1	-	-
Walker	2020	UK	94	-	-	7.6	3.1–16.0	0-112
Maconi	2015	Italy	83	41	35.2 (14.5)	8	(3–27)	[0-324]
Vavricka	2012	Switzerland	932	46.8	41 (15), [16–88]	9	(3–24)	-
Nguyen	2017	USA	110	41.0	35 (17)	9.5	(3.8–25.6)	-
Li	2015	China	343	70.0	29.5 (12.0)	10	(2–34)	-
Pellino	2015	Italy	361	Not reported	32.54 (14.47)	11	-	[1-163]
Irving	2018	Finland, Italy, France, Canada, Germany, UK, Spain and Sweden	4097	Not reported	Not reported	12	-	0-564
Albert	2008	Germany	112	34.8	28 (8.0) F 31 (11.5) M	13	-	[0-281]
Banerjee	2018	India	720	60.3	32 (18–50)*	18	(6–36)	-
Gomes	2021	Brazil	303	49.8	32	20	6.5–48	-
Lind	1985	Norway	214	56.1	24, [7–63] 22*	24
Szanto	2018	Hungary	428	45.3	26.6 (11.3)	25.2	0-103.2
Munkholm	1992	Denmark	373	42.1	32.5, 8–84	26.4		0-324
Burgmann	2006	Canada	65	33.8	38 (12.9), [16–77]	84
Ulcerative Colitis (UC)
Guariso	2010	Italy	99	-	-	2	-	0-135
Basaranoglu	2015	Turkey	98	52.0	37.8 (13.5), [17–79]	2		0–15
Cantoro	2017	Italy	1855	53.1	Not Reported	2
Chaparro	2021	Spain	1964	50.1	46^† (34–57)	2		1–5
Kang	2019	South Korea	551	55.7	40.56 (16.11)	2.3
Romberg-Camps	2009	Netherlands	476	39.3	34, 5–79	3		0-480
Nahon	2018	France	272			3
Nguyen	2017	USA	110	41.0	38 (17)	3.1	1.1–9.6
Walker	2020	UK	195	-	-	3.3	1.9–7.3	0–65
Novacek	2019	Austria	830	48.1	40 (31–52)*	3.4	1.4–10.3
Vavricka	2012	Switzerland	932	46.8	41 (15), [16–88]	4	1–12
Yang	2000	Korea	94	47.9	35*, [8–68]	6		1-120
Gomes	2021	Brazil	355	38.3	35.3	11	4–29
Irving	2018	Finland, Italy, France, Canada, Germany, UK, Spain and Sweden	3410	Not reported	Not reported	12		0-552
Langholz	1991	Denmark	1161	46.7	34, [2–88]	12		0-444
Szanto	2018	Hungary	428	45.3	26.6 (11.3) 30.9 (12.5)	55.2	0-123.6
Burgmann	2006	Canada	65	33.8	38 (12.9), [16–77]	114
IC- Indeterminate Colitis; IBD-U- Unclassified Inflammatory Bowel Disease; SD- Standard Deviation; IQR- Interquartile Range * Median age reported with interquartile range. Studies in italic indicates outliers. ^†=Median age provided

Through the sensitivity analysis one article was excluded due to consistently being an outlier across the three condition groups. Burgmann et al. [5] reported median delays of approximately 60–75 months longer than the next closest study across the three analyses. After exclusion of this outlier, the median diagnostic delay of IBD across the remaining 8 articles ranged from 2 to 13 months, with three quarters of these reporting a delay of between 2-5.3 months. Of the 23 studies defining samples solely by CD, the overall delay ranged from 2 to 26.4 months, with three quarters of the reported median delays ranging from 2–12 months. Finally, from the16 studies examining UC, median diagnostic delay ranged from 2 to 55.2 months, with two thirds of studies reporting delay between 2 to 6 months. This overall longer median delay observed in patients with CD compared to UC was also observed in the subset of studies where delay had been directly compared between the two conditions within the same populations [5, 7, 13, 21, 24, 34].

Factors associated with diagnostic delay

Three studies compared differences in delay related to help-seeking (from symptom onset to primary health care consultation) and that which occurred after the first consultation. Though Vavricka found that delay was significantly greater for CD than UC patients during the help-seeking and first consultation phase, Nguyen only found delay after first consultation to final diagnosis to be significantly greater for CD patients compared to UC patients [6, 14]. Walker [28] reported longer delays across help-seeking, primary care and secondary care in CD over UC (Table 3).

Table 3

Extent of delay in IBD diagnosis at different stages of the patient journey
				Median months of delay (IQR) [range]
Reason for delay	Reason/point of delay	Author, year	Country	CD	UC
Patient-related delay	Non-help-seeking	Vavricka, 2012	Switzerland	2 (0–6)	1 (0–4)
		Nguyen, 2017	USA	1 (0.2–4.9)	0.7 (0.3–3.0)
		Lee, 2017	South Korea	1.2 (0.5–8.4)	1.9 (0.9–4.9)
		Walker, 2020	UK	3 (0.9–6.7)	2.1 (0.9–3.9)
Healthcare-related delay	Delay following first consultation	Nguyen, 2017	USA	3.5 (1.2–20.5)	1.1 (0.4–5.4)
	Delay following first consultation	Vavricka, 2012	Switzerland	4 (0–18)	1 (0–5)
	Delay from first physician visit to IBD diagnosis	Lee, 2017	South Korea	0.7 (0.1–4.6)	0.2 (0.1–0.6)
	Primary care delay	Walker, 2020	UK	0.3 (0.0-1.2)	0.2 (0.0-0.8)
	Secondary care delay	Walker, 2020	UK	1.6 (0.6–3.7)	0.9 (0.5-2.0)

Three articles found statistical significance between increasing age and longer diagnostic delay [8, 25, 30]. The study by Foxworthy and Wilson was the only one that reported median values, showing a statistically significant difference in diagnostic delay of CD between patients over 60 (diagnostic delay 16 months) and patients less than 60 years old at diagnosis (diagnostic delay 5 months) [30].

A prospective cohort study conducted by Burisch et al. grouped data from 14 Western and 8 Eastern European countries to compare differences in diagnostic delay [9]. For CD, median values of diagnostic delay were 4.6 and 3.4 months, respectively, for Western and Eastern Europe. Diagnostic delay was 2.5 and 2.2 months for UC in Western and Eastern Europe, respectively (Table 4). However, these differences were not statistically different.

Table 4

Data for additional characteristics of delay
Author, Publication Year and Country	CD/UC	Diagnostic Criteria	Comparison	Sample Size	% Male	Mean Age (SEM), range	Diagnostic Delay (SD)/range (months)
Foxworthy (1985), USA	CD	Chart review	Diagnosis ≥60 years old	10	50%	68 (1.6), 60–78	Median- 16
Foxworthy (1985), USA	CD	Chart review	Diagnosis < 60 years old	20	35%	27 (1.6), 20–45	Median- 5
Harper (1986), USA	CD	Clinical/radiologic/ endoscopic/ operative features	Diagnosis > 64 years old	24	42%	57 (2.5)	Mean- 76.8 (18)
Harper (1986), USA	CD	Clinical/radiologic/ endoscopic/ operative features	Diagnosis < 64 years	24	42%	23.3 (2.0)	Mean- 28.8 (8.4)
Lin (2016), Taiwan	UC	Not reported	Onset ≥60 years old	77	60%	68 (6.0), 60–91	Mean- 26.4 (54), 0- 288
Lin (2016), Taiwan	UC	Not reported	Onset < 60 years old	459	59%	36.8 (11.5), 1–59	Mean- 4.8 (9.6), 0-120
Burisch (2014), Europe	CD	Copenhagen diagnostic criteria	Western Europe	430	51%	38, 16–89	Median- 4.6, 0-372
	CD	Copenhagen diagnostic criteria	Eastern Europe	105	60%	32, 15–78	Median- 3.4, 0-240
	UC	Copenhagen diagnostic criteria	Western Europe	668	56%	39, 15–89	Median- 2.5, 0-252
	UC	Copenhagen diagnostic criteria	Eastern Europe	145	57%	36, 18–81	Median- 2.2, 0–60
ECCO-ESGAR = European Crohn’s and Colitis Organisation [ECCO] and the European Society of Gastrointestinal and Abdominal Radiology [ESGAR]

This systematic review demonstrates that receiving a prompt diagnosis of IBD remains difficult to achieve, with patients typically experiencing several months of diagnostic delay. In particular, delay is prolonged in patients with CD compared to UC, with the majority of previous studies reporting diagnostic delay less than 12 months for CD, but less than 6 months for UC. However, research examining the specific factors contributing to delay in either condition remains very limited. Ultimately, this data provides a new benchmark against which interventions to reduce delay in patients with IBD can be compared.

The skewed nature of diagnostic delay data means that (for the majority) of patients with CD or UC, diagnosis is achieved within a year of symptom onset. However, one in four studies did find that, on average, receiving a final diagnosis of CD could take between 12 to 24 months from the initial onset of symptoms, whereas we identified that three quarter of patients with UC were diagnosed in < 6 months. These findings provide a more accurate understanding of the true extent of diagnostic delay and though not intended to minimise the problem of diagnostic delay in UC, the greatest impact in a reduction in delay for patients with IBD may come from focusing on CD.

Our reported findings are based on the studies included in the sensitivity analysis, rather than all identified studies. By removing the study by Burgmann et al, [5] which reported extremely protracted delays in IBD, CD and UC diagnosis, we have provided a more representative median range for diagnostic delay. Though removal of such outliers is a somewhat arbitrary one, performing this practical sensitivity analysis enabled us to look at the most common length of delay. To support the removal of this studies based on their reported, extreme delay values, we examined the details of the study design but could not identify any clear reason why their data was drastically different to that of the other studies in the systematic review. However, it was of note that this study reported longer diagnostic delay in UC compared to CD, contrary to other included studies.

Possible reasons for UC consistently demonstrating shorter diagnostic delays than CD could be because the location of disease is confined to the large bowel and patients experiencing rectal bleeding may be more likely to present to a doctor [7]. However, CD delays may be longer due to a lack of clinical suspicion and diagnostic testing, associating common CD symptoms like abdominal pain with other conditions such as irritable bowel syndrome and difficulties in identifying disease that is only present in the small bowel [12, 14, 40].

Though overall diagnostic delay in patients with IBD, CD or UC has frequently been reported in the literature, there remains a dearth of data to have examined the role of specific patient or healthcare factors in contributing to delay. Such sub-analysis has proven useful in other systematic reviews into diagnostic delay, as this provides focus on certain characteristics which could prove to be avenues to reduce delay. For example, a previous systematic review on diagnostic delay in giant cell arteritis found delay was greater in those patients who did not experience cranial symptoms compared to those with cranial symptoms [16]. However, there remains a lack of evidence in such sub-analysis in IBD populations and despite our identification of studies to have considered the role of age at diagnosis and sample country, findings were limited and conflicting.

Research exploring the barriers and facilitators to IBD diagnosis is clearly needed. Diagnostic delay has been explored in many other studies for a variety of conditions, including giant cell arteritis, gynaecological cancers and tuberculosis [16, 43, 44]. Exploring the extent of diagnostic delay in medical conditions, where delays are common, is important as it provides a backdrop for future research examining the reasons for prolonged diagnostic delay and potentially inform interventions for reducing delays and improving patient care. As prolonged diagnostic delay of IBD appears to increase the likelihood of complicated disease, reducing delays in IBD diagnosis could improve the clinical outcome of patients with the condition [12, 45]. The specific use of the faecal calprotectin test was not discussed in the studies of this systematic review. It detects levels of calprotectin within stool as a consequence of neutrophil aggregation to the gastrointestinal tract due to active inflammation like that found in IBD [46]. Existing research suggests that this is effective at differentiating between organic and functional origins of bowel disease, thus could reduce delays in IBD diagnosis [47, 48].

The focus on median data within the analysis in this systematic review is a key strength as it reduces problems related to overestimation of averages typically related to use of means from skewed data, providing a more robust estimate of diagnostic delay. Furthermore, as well as examining IBD overall, this systematic review examined the most common disease sub-categories of UC and CD, and, finally, we did not restrict study inclusion based on language, leading to additional studies being included in the review. A limitation of this study is the variation between individual study designs, for instance differences in participant age, method of IBD diagnosis and country. However, despite the introduction of such heterogeneity, this data also provides a wider picture of the problem of diagnostic delay in this disease group.

In conclusion, this systematic review provides a robust insight into the current extent of diagnostic delay in IBD, indicating that diagnostic delay remains a pertinent issue for patients with IBD, particularly CD, but that the factors which may have a role in delay remain unclear. This systematic review provides a backdrop and benchmark onto which further research can be conducted to reduce the time to IBD diagnosis, particularly exploring knowledge of IBD amongst healthcare professionals and the general population to help reduce overall delay. This future research is particularly important, as reducing diagnostic delay of IBD may improve the clinical course of the disease.

Acknowledgements

The authors would like to thank the systematic review team (Dr Nadia Corp and Dr Opeyemi Babatunde) at Keele University School of Medicine for their advice and assistance in the completion of this systematic review. They also wish to thank Dr Kay Polidano who was involved in the translation of selected articles.

Conflict of Interest

The authors declare no conflict of interest

Funding

No funding is associated with this publication

Author contributions

EC: Creation of search strategy, database search, data extraction, article review, narrative synthesis, writing of manuscript

JAP: Initial study design, creation of search strategy, data extraction, article review, narrative synthesis, writing of manuscript

BS: Initial study design, article review, writing of manuscript

ADF: Initial study design, clinical input, article review, writing of manuscript

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Supplementary Table 1- Search strategy:

Search Strategy
1	Exp inflammatory bowel diseases/
2	inflammatory bowel disease*.ti,ab,kw.
3	inflammatory bowel disorder*.ti,ab,kw.
4	ibd.ti,ab,kw.
5	crohn*.ti,ab,kw.
6	ulcerative colitis*.ti,ab,kw.
7	inflam* colitis*.ti,ab,kw.
8	colitis*.ti,ab,kw.
9	colitis/
10	1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9
11	diagnos* adj3 delay*.ti,ab,kw.
12	diagnos* adj3 lag*.ti,ab,kw.
13	diagnos* adj3 interval*.ti,ab,kw.
14	((late* or earl) adj3 diagnos).ti,ab,kw.
15	((late* or earl) adj3 treat).ti,ab,kw.
16	((late* or earl) adj3 consult).ti,ab,kw.
17	((late* or earl) adj3 refer).ti,ab,kw.
18	((late* or earl) adj3 detect).ti,ab.kw.
19	(health* adj3 seek*).ti,ab,kw.
20	(case* adj3 seek*).ti,ab,kw.
21	(case* adj3 find*).ti,ab,kw.
22	(delay* adj3 consult*).ti,ab,kw.
23	(delay* adj3 detect*).ti,ab,kw.
24	(delay* adj3 interval*).ti,ab,kw.
25	(delay* adj3 refer*).ti,ab,kw.
26	(delay* adj3 treat*).ti,ab,kw.
27	(delay* adj3 seek*).ti,ab,kw.
28	Delayed diagnosis/
29	Early diagnosis/
30	11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29
31	10 AND 30

No competing interests reported.

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Diagnostic Delay in Adult Inflammatory Bowel Disease: A Systematic Review

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Factors associated with diagnostic delay

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