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Diagnostic delay in Crohn's disease is associated with increased rate of abdominal surgery: A retrospective study in Chinese patients
Digestive and Liver Disease, Volume 47, Issue 7, July 2015, Pages 544–548
Diagnostic delay of Crohn's disease presents a challenge, and may increase the abdominal surgery rate. There have been no reports regarding diagnostic delay in Chinese patients.
We aimed to evaluate the impact of diagnostic delay on outcomes of Chinese Crohn's disease patients, and identify potential risk factors for the delay.
Altogether, 343 Crohn's disease patients from our hospital were retrospectively included. We assessed the effects of diagnostic delay on the outcomes, and identified the underlying risk factors.
Diagnostic interval was defined as the interval between the first symptoms and the diagnosis of Crohn's disease. Diagnostic delay was defined according to the time interval in which the 76th to 100th percentiles of patients were diagnosed. The rates of subsequent surgery for diagnostic-delay and non-diagnostic-delay patients were 84.7% and 62.4%, respectively (odds ratio = 1.108, P < 0.0001). We found statistical differences between the two groups regarding age >40 years at diagnosis (35.3% versus 18.2%, P = 0.004), basic educational level (48.2% versus 30.6%, P = 0.005), and no family history of Crohn's disease (0 versus 1.6%, P = 0.045).
Diagnostic delay of Crohn's disease was significantly associated with increased rates of intestinal surgery. Risk factors for diagnostic delay were age >40 years at diagnosis, basic educational level, and no family history of Crohn's disease.
Keywords: Crohn's disease, Diagnostic delay, Intestinal surgery, Risk factor.
Crohn's disease (CD) is a chronic, recurrent, inflammatory bowel disease and its prevalence has increased annually worldwide. Europe and America are traditionally high-risk areas  , but also the incidence of CD in traditionally low-risk regions, such as Asia, is rapidly growing  . CD could become an important public health issue, also because early diagnosis and essential treatment are crucial to the patients’ prognosis.
Large disparities among countries exist in the diagnostic level of CD, due to factors such as economy, geographic distribution, medical education, public literacy, and others. Thus, diagnostic delay of CD is a challenge in several parts of the world , , , and ; however, to our knowledge, there are no reports investigating diagnostic delay in Chinese patients with CD. If CD patients do not seek timely medical treatment, or if physicians do not make a definitive diagnosis in a timely fashion, the course of CD may change. A delayed diagnosis could result in missing the best timing for treatment, thus affecting the prognosis and increasing the risk of CD-related surgery. The aim of this study was to determine the incidence of diagnostic delay of CD, identify the associated risk factors for the delay, and explore its impact on the outcomes in a population of Chinese patients with CD.
2. Materials and methods
A retrospective study was performed on 417 patients with a definitive diagnosis of CD registered at the Department of General Surgery of the Jinling Hospital, China, between September 2010 and August 2014. We assigned a definitive diagnosis of CD based on the results of colonoscopy, small bowel capsule endoscopy, enteroscopy, upper endoscopy, computed tomography enterography, histopathological examination, blood tests (including routine blood examination, erythrocyte sedimentation rate, C-reactive protein, autoimmune-related antibodies), and other examinations. Overall, 54 patients were excluded from this study; among these, 32 were lost to follow-up, 20 failed to provide the exact date of diagnosis, and 22 were diagnosed within 1 year of the start of our study. Not all the patients enrolled were initially diagnosed as having CD at our hospital. Thus, for those referred from other medical institutions, we obtained and scrutinized their previous medical records, including the diagnostic information (especially the exact date of CD diagnosis). The Ethics Committee of the Jinling Hospital approved this study.
The parameter “diagnosis time” for CD consisted of two parts: (1) the interval between the appearance of the first CD symptoms and the first visit to the physician (patient-related phase) and (2) the interval between the first visit to the physician and the CD diagnosis (physician-related phase). The diagnostic interval was defined as the time (in months) elapsed between the first appearance of symptoms and the CD diagnosis. To define the entire disease duration, we defined “symptoms onset” as the earliest time in which CD-related symptoms occurred. The exact time of onset was obtained from the medical records.
Referring to the previous studies of the Swiss inflammatory bowel disease cohort  and , the diagnostic delay in our paper is defined according to the time interval in which the 76th to 100th percentile of Crohn's disease patients were diagnosed.
We assessed the possible risk factors contributing to diagnostic delay and the potential effects of the delay on the risk of the following outcomes: development of bowel stenoses, internal fistulas, or perianal fistulas, as well as the need for intestinal surgery, perianal surgery, or other types of surgery. All these outcomes have an impact on the prognosis of CD  and .
The patients’ data were collected both from the electronic database of the Jinling Hospital and from follow-up telephone calls. The data included the patient's gender (male vs. female), educational level (basic vs. higher, see additional explanations below), origin (urban vs. rural), regular rest (yes vs. no, see additional explanations below), age at first symptoms, age at diagnosis (≤40 vs. >40 years), initial disease location (according to the Montreal classification), nonsteroidal anti-inflammatory drug (NSAID) intake at the time of the first symptoms (yes vs. no), steroid intake at first symptoms (yes vs. no), smoking status at diagnosis (yes vs. no), extra-intestinal manifestation (EIM) at diagnosis (present vs. absent), and CD family history (present vs. absent).
“No education at all” and “elementary school” were defined as the “basic education level” compared with “higher education level,” which included high school, higher vocational education, university, and higher degrees. “Regular rest” indicated that the work and rest times were relatively fixed. EIMs indicated the involvement of the skin and mucosa, eyes, joint, liver, and other organs. The manifestations included oral ulcers, iritis, uveitis, reactive arthritis, nodular erythema, and primary biliary cirrhosis, among others  .
The study population was divided into two groups: the diagnostic-delay group (patients who had a diagnostic delay) and the non-diagnostic-delay group (patients who did not have a diagnostic delay). We then compared the demographics and clinical characteristics of the two groups.
2.2. Statistical analysis
All statistical analysis was performed with IBM SPSS Statistics, Version 22.0.0 (IBM, Armonk, NY, USA). Quantitative data are presented as mean ± SD for parametric data. Categorical data are reported as percentages. Differences in quantitative data distributions between the two groups were compared using Student's t-test (for parametric data) and the Wilcoxon rank-sum test (for non-parametric data). Differences of frequencies for categorical data were compared using the χ2 test, or Fisher's exact test in case of a small sample size (n < 5 per group). To determine the variables associated with complications, multivariate logistic regression analyses were performed, and odds ratios were estimated with the associated P values. A P < 0.050 was considered to indicate statistical significance.
3.1. Demographics and clinical characteristics of the study population
The demographics and clinical characteristics of the study population are shown in Table 1 . Briefly, of the 343 patients, 240 (70.0%) were males, 120 (35.0%) had only a basic educational level, 253 (73.8%) lived in urban areas, and 11 (3.2%) did not have regular rest. The average age at onset of symptoms was 29.5 ± 12.0 years, and the average age at diagnosis was 31.8 ± 12.5 years. In all, 266 (77.5%) patients were diagnosed at an age ≤40 years. The disease locations (according to the Montreal classification) are shown in Table 1 : most of the lesions were located in the ileum (L1) and the ileocolonic area (L3). A total of 18 patients (5.2%) had a history of NSAID intake when they first experienced their symptoms. At the time of diagnosis 57 patients (16.6%) were smokers. In all, 114 patients (33.2%) had EIMs during the disease course, and only four patients (1.2%) had a family history of CD. When comparing the medication history between the two groups, the differences did not reach statistical significance ( Table 2 ).
|Characteristic||The total study population (N = 343)||Non-diagnostic-delay group (N = 258)||Diagnostic-delay group (N = 85)||P|
|Male gender||240 (70.0%)||180 (69.8%)||60 (70.6%)||0.887|
|Basic educational level||120 (35.0%)||79 (30.6%)||41 (48.2%)||0.005|
|Urban||253 (73.8%)||194 (75.2%)||59 (69.4%)|
|Rural||90 (26.2%)||64 (24.8%)||26 (30.6%)|
|Regular rest||332 (96.8%)||249 (96.5%)||83 (97.6%)||0.608|
|Mean age at first symptoms (years)||29.5 ± 12.0||29.7 ± 12.1||28.8 ± 11.8||0.515|
|Mean age at diagnosis (years)||31.8 ± 12.5||30.4 ± 12.1||35.7 ± 12.9||0.001|
|Mean age at diagnosis >40 years (no.)||77 (22.4%)||47 (18.2%)||30 (35.3%)||0.004|
|Mean disease duration from CD diagnosis (months)||84.3 ± 50.8||85.0 ± 57.4||0.913|
|Initial disease location||0.263|
|L1 (ileal)||145 (42.3%)||111 (43.0%)||34 (40.0%)|
|L2 (colonic)||64 (18.7%)||52 (20.2%)||12 (14.1%)|
|L3 (ileocolonic)||111 (32.4%)||79 (30.6%)||32 (37.6%)|
|L4 (upper GI tract)||23 (6.7%)||16 (6.2%)||7 (8.2%)|
|NSAID use at first symptoms||18 (5.2%)||11 (4.3%)||7 (8.2%)||0.225|
|Current smokers at diagnosis||57 (16.6%)||42 (16.3%)||15 (17.6%)||0.770|
|EIM||114 (33.2%)||89 (34.5%)||25 (29.4%)||0.390|
|Family history||4 (1.2%)||4 (1.6%)||0||0.045|
CD, Crohn's disease; GI: gastrointestinal; NSAID, non-steroidal anti-inflammatory drugs; EIM, extra-intestinal manifestations.
|Treatment||Total (N = 343)||Non-diagnostic-delay group (N = 258)||Diagnostic-delay group (N = 85)||P|
|Sulfasalazine||158 (46.1%)||125 (48.4%)||33 (38.8%)||0.121|
|Mesalazine||105 (30.6%)||78 (30.2%)||27 (31.8%)||0.793|
|Corticosteroids||94 (27.4%)||71 (27.5%)||23 (27.1%)||0.934|
|Immunosuppressants||37 (10.8%)||28 (10.9%)||9 (10.6%)||0.946|
|Enteral nutrition||328 (95.6%)||245 (95.0%)||83 (97.6%)||0.212|
|Infliximab||10 (2.9%)||7 (2.7%)||3 (3.5%)||0.699|
As a patient may have undergone a combination of treatments, the percentage totals more than 100%.
3.2. Diagnostic delay
The average diagnostic interval was 29.0 ± 44.3 months. The first quartile was 2 months, the second quartile (median) was 10 months, and the third quartile was 34 months. According to the division standard of the Swiss inflammatory bowel disease study  , the diagnostic interval for CD was defined as the diagnostic delay, and was more than 34 months in our study (third quartile of diagnostic intervals). The patient-related delay was more than 5 months and the physician-related delay more than 21 months.
3.3. Impact of diagnostic delay on complications
The rate of subsequent surgery for the diagnostic-delay group was 84.7%, whereas in the non-diagnostic-delay group it was 62.4%. The types of intestinal surgery performed are shown in Table 3 (note that since some patients underwent more than one operation, the percentage totals more than 100%.) Regarding complications in the two groups, only the differences in internal surgery performance reached statistical significance (P < 0.0001). Thus, stenosis, perianal fistula, internal fistulas, perianal surgery, and other types of surgery were not significantly different between the groups ( Table 4 ).
|Previous intestinal surgery||No.|
|Ileal resection||48 (14.0%)|
|Ileocecal resection||46 (13.4%)|
|Resection of other parts of the small bowel||95 (27.8%)|
As a patient may have undergone several operations, the percentage totals more than 100%.
|Complication||Non-diagnostic-delay group (N = 258)||Diagnostic-delay group (N = 85)||P|
|Stenosis||118 (45.7%)||41 (48.2%)||0.690|
|Perianal fistula||34 (13.2%)||14 (16.5%)||0.143|
|Internal fistula||63 (24.4%)||28 (32.9%)||0.449|
|Perianal surgery||37 (14.3%)||11 (12.9%)||0.748|
|Internal surgery||161 (62.4%)||72 (84.7%)||<0.0001|
|Other types of surgery||68 (26.4%)||30 (35.3%)||0.132|
The multivariate logistic regression analysis showed that diagnostic delay was significantly associated with the performance of internal surgery (OR = 1.108, P < 0.0001) ( Table 5 ).
|Factor||Odds ratio||95% confidence interval||P|
|Age at diagnosis||0.337|
|≤40 years||1 (Ref)||–|
3.4. Impact of disease-associated factors on diagnostic delay
Comparing the two groups, we found that there were no statistically significant differences regarding patient gender, origin, regular rest, age at first symptoms, initial disease location, NSAID intake at first symptoms, steroid intake at first symptoms, smoking status at diagnosis, or EIM. The only factors that were significantly different between the groups were age at diagnosis >40 years, having only a basic education, and no family history of CD ( Table 1 ). The disease duration from CD diagnosis in the diagnostic-delay and non-diagnostic-delay groups were similar ( Table 1 ).
This study indicated that diagnostic delay is significantly associated with an increased rate of subsequent surgery. We also found that the risk factors for diagnostic delay in CD patients were age >40 years at diagnosis, having only a basic educational level, and no family history of CD. This is the first study to demonstrate not only the impact of diagnostic delay on outcomes in CD patients but also the risk factors for diagnostic delay and its prevalence in China.
In this study, the majority of the patients were males (70.0%), consistently with our previous epidemiological study  . Also other studies, conducted in Korean  and Japanese  populations, showed a similar male predominance among CD patients. By contrast, Western studies presented a moderate female predominance or a generally equal gender distribution among CD patients; this might be explained by ethnic differences.
We found no statistically significant differences between the two groups regarding medication use or disease duration from CD diagnosis. Therefore, we could exclude the impact of medical treatment and the follow-up period as affecting factors.
The diagnostic delay in this study (34 months) was longer than that reported for a Swiss population (24 months)  . Compared with the Swiss study, our patient-related delay was somewhat shorter (5 months vs. 6 months), while the physician-related delay was longer (21 months vs. 18 months). With the gradual improvement of the living standards in China, people have begun to pay more attention to their health problems. This has been facilitated by our currently improved health care system, which allows easier access to physician visits  . Thus, people can receive health services when their CD symptoms begin, thereby shortening the patient-related delay. However, the longer physician-related delay we here report suggests that the Chinese medical standards and diagnostic levels regarding CD are far behind those of other countries  .
Schoepfer et al.  found that diagnostic delay in CD leads to multiple serious consequences, especially intestinal stenosis and a significantly increased risk of surgery. In our study, we found that diagnostic delay is associated with an increased risk for CD-related intestinal surgery.
Since the present retrospective study originated from a surgical department, the majority of patients (81.9%) visited our department with surgical complications (e.g. stenosis and penetrating complications), thus implying a relatively higher probability of surgery in this population. Therefore, we are currently considering conducting a prospective multidisciplinary study to obtain information in this regard among the general population. Despite the limitations of the current study, our findings do suggest negative effect of a delayed diagnosis.
The risk factors for diagnostic delay in our Chinese CD patients were different from those reported in a Swiss population  . Schoepfer et al.  found that their risk factors for diagnostic delay were age at diagnosis <40 years, presence of ileal disease, female gender, smoking history, and not taking NSAIDs.
These differences relate to unique factors present in China, among which the fact that CD diagnosis is more common in young people (age <40 years). In fact, young patients are highly suspected to have CD if they complain of abdominal pain, diarrhoea, weight loss, and other common symptoms of CD  . By contrast, older patients (age >40 years) with these same complaints are often misdiagnosed as having chronic colitis  , intestinal cancer  , or another intestinal disease, thus significantly increasing the risk of a diagnostic delay for CD. Secondly, compared with patients who have only a basic educational level, the more highly educated ones tend to pay more attention to their health problems, and are thus more likely to be admitted to a hospital. Last, if patients report a family history of CD, diagnosis is more easily suspected  by both patients and physicians.
In recent years, a wide variety of immune inhibitors have been used clinically  along with stem cell therapy  and enteral nutrition  therapy, thus providing new ways to treat CD. Early treatment in the disease course could effectively relieve symptoms, maintain the disease in remission, improve the patient's quality of life, and reduce the probability of future CD-related surgery  and . By contrast, when the diagnosis is delayed, the clinical course of CD changes, reducing the patient's susceptibility to drug treatment and significantly increasing the probability of CD-related surgery  . Surgical intervention has been considered an indicator of serious CD. Although timely surgery can effectively alleviate the illness and improve quality of life, it cannot cure the disease and can significantly increase the patients’ economic burden  . Thus, overall, medical workers should try to avoid CD-related operations.
This is the first report analyzing the diagnostic delay of CD in Chinese patients. Similar studies have been performed in Switzerland  and , the Netherlands  , and France  . Considering the heterogeneous characteristics of CD in the ethnic groups previously considered, this study conducted in Chinese CD patients could contribute to a better understanding and management of diagnostic delay of CD.
Nevertheless, some limitations exist in this study: due to the small sample size recruited from a single centre, and the study's retrospective design, there is a potential risk of selection bias and loss to follow-up bias. Thus, our results may not completely reflect the actual risk factors and impacts of diagnostic delay.
A better understanding of the effects of diagnostic delay for CD patients is urgently needed. We also need to arouse the concern of the general public and medical workers about avoiding such delays, which can contribute to a poor prognosis. In conclusion, the prognostic importance of diagnostic delay in CD should be emphasized and appropriate measures to reduce this delay should be implemented.
Conflict of interest
This study was supported by the National Natural Science Foundation of China (81270478).
The authors are grateful to Le Yu, who greatly helped to make this study a reality; and to You Xu, for the support and time dedicated during the difficult course of the study.
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Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
⁎ Corresponding author at: Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing 210002, China. Tel.: +86 13605169808.
© 2015 Editrice Gastroenterologica Italiana S.r.l., Published by Elsevier B.V.