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Original Research

Seasonal clustering in inflammatory bowel disease: a single centre experience Expert Rev. Gastroenterol. Hepatol. 9(6), 877–881 (2015)

Metin Basaranoglu*1,2, Abdurrahim Sayilir2, Ali E Demirbag3, Sanju Mathew4, Aftab Ala4,5 and Hakan Senturk1 1 Department of Gastroenterology and Hepatology, Bezmialem Vakif University Faculty Hospital, Fatih, 34000, Istanbul, Turkey 2 Gastroenterology Division, Tu¨rkiye Yu¨ksek Ihtisas Hospital, Sihhiye, 06010, Ankara, Turkey 3 Gastrointestinal Surgery Division, Tu¨rkiye Yu¨ksek Ihtisas Hospital, Sihhiye, 06010, Ankara, Turkey 4 Department of Gastroenterology and Hepatology, Royal Surrey County Hospital, Guildford, Surrey, UK 5 Faculty of Health and Medical Sciences, Faculty of Health Management and Strategy, University of Surrey, Surrey, UK *Author for correspondence: Tel.: +90 212 554 0000 Fax: +90 212 554 0000 [email protected]

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Backgrounds and aims: External stimuli are considered as possible triggers for the onset of inflammatory bowel disease (IBD), and particularly chronic ulcerative colitis (CUC) in genetically susceptible individuals. Our aims were to investigate monthly clustering-patterns in the onset of symptoms and diagnosis of IBD, as well as health seeking behavior in those individuals. Materials and methods: Two hundred and eighty-two consecutive patients with IBD were included. Onset of symptoms (month) and delay to diagnosis were analyzed. Kruskal–Wallis and Roger’s test were used to analyze for statistical patterns in seasonal clustering. Results: There were 181 males and 101 females with IBD; mean age: 40 ± 14.7 years (median: 38, range: 14–79 years). The peak number of IBD cases was seen in winter/early spring, with the lowest numbers in autumn, which reached statistical significance in the CUC group (p: 0.029). Seasonal changes were not significantly affected by gender. The time delay to diagnosis from symptom onset was 3.0 ± 2.3 months in males (median: 2, range: 0–12 months) vs 3.2 ± 3.2 months (median: 2, range: 0–18 months) in females (not statistically significant). Conclusion: Our results show a seasonal relation in IBD cases, particularly in CUC, which may suggest external stimuli acting as a precipitant to IBD in susceptible individuals. There was a delay between symptom onset and CUC diagnosis, which was not felt to be clinically significant. KEYWORDS: chronic ulcerative colitis . delayed diagnosis . inflammatory bowel diseases

Backgrounds & aims

External stimuli have been considered as triggers to the onset of chronic ulcerative colitis (CUC) in genetically susceptible individuals [1]. In this regard, the investigation of seasonal cluster in CUC is very timely and necessary [2–8]. Monthly clustering patterns in flares of inflammatory bowel disease (IBD) have been previously reported [9–15]. However, very few studies have investigated seasonal variability, and then only in Western populations [1–8]. Additionally, previous studies have often incorrectly used endoscopic diagnostic dates (including histological and radiological findings), which should not be used to assess the occurrence of seasonal variation [16,17]. The few studies that exist according to the above criteria do suggest some seasonal association with CUC, but have not shown such variation with Crohn’s disease (CD), and overall are not in harmony [7,8].

10.1586/17474124.2015.1025054

.

seasonal variation

There is also a belief that the risk factors of IBD in the East differ from the West. So far, the seasonality of IBD has not been reported in Eastern countries. Turkey is a country that straddles two continents, lying 97% within Asia as well as bordering Europe and represents a unique opportunity to explore the seasonality of IBD in this Eastern population [18]. In this study, our main purpose is to investigate monthly clustering in the onset of symptoms in CUC, as well as the time delay to established CUC diagnosis. Materials & methods Study population

This is a retrospective cohort study, which utilizes a chart review system that we have had in place in our tertiary IBD center since 1995. This study was approved by the Health Directorate. Ethical approval was not required for this study because the data used was retrospectively

 2015 Informa UK Ltd

ISSN 1747-4124

877

Original Research

Basaranoglu, Sayilir, Demirbag, Mathew, Ala & Senturk

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Table 1. Characteristics of the study population are shown. CUC

CD

IBD

P

Age (years)

41.4 ± 15.2 (median: 40.5; range:14–78)

37.8 ± 13.5 (median: 36; range: 17–79)

40.1 ± 14.7 (median: 37.8; range: 14–79)

NS

Gender

71% male (130 patients)

52% male (51 patients)

64% male

NS

Type of disease site

29% proctitis 34% left side CUC 37% extensive CUC

45% colon alone 31% ileocolon 24% small bowel alone

Of the 282 patients with IBD, 181 patients were male (64%). Of the 98 patients with CD, 51 patients were male (52%). There were 184 patients with CUC; with 130 males (71%). Male patients were more prominent in the CUC group, without reaching statistical significance. The median age of patients with CUC (~40 years) was higher than that in patients with CD (36 years), but without reaching statistical significance. CD: Crohn’s disease; CUC: Chronic ulcerative colitis; IBD: Inflammatory bowel diseases; NS: Not statistically significant (p > 0.05).

collected from existing patient records. All patients were of Turkish origin, with data collected over a 12-year period. Patient characteristics and the symptoms (diarrhea, fever, abdominal pain and cramping, bloody stool or weight loss) at presentation were recorded for all IBD patients, as well as the delay in reaching a formal diagnosis. IBD was established when clinical, endoscopic and radiological findings were supported by histological evidence. The date of clinical presentation with symptoms was used for analysis and to estimate monthly IBD clustering. Climate features of Turkey & definition of seasons

We performed this study in Ankara, Turkey, which is located in the Asian part of Turkey. The seasons (quarters) are defined as: winter (January, February and March), spring (April, May and June), summer (July, August and September) and autumn (October, November and December). Data analysis

The data were coded and recorded using IBM Statistical Package for the Social Sciences (SPSS; Armonk, NY), Windows version 17.0 (2007). The monthly distribution of symptoms was used to investigate clustering by cumulative diagnosis per month during the 12-year study period. The graphical data presentation was based on the cumulative monthly means, expressed as the percentage above or below the mean monthly value during the entire study period [16,18]. The amplitude of seasonal variation was described by the total seasonal variation. Total seasonal variations were measured as the sum of the percentage above the average for the month with the highest value and the percentage below the average for the month with the lowest value. Statistical methods

Kruskal–Wallis test and Roger’s test for cyclic variation were used to determine any seasonal variation of incidence [16,18]. This statistical analysis determines a simple harmonic cyclic trend, by dividing a circle into 12 equal sectors and plotting the monthly frequencies as coordinates (x and y) in the corresponding sectors in the circle. Otherwise, c2, Student’s t-test and Mann–Whitney U analyses were used. Probability (p) values 0.05). However the median age of patients with CUC (~40 years) was higher than that of patients with CD (36 years) (p > 0.05). The seasonal pattern of IBD showed a peak number of cases in early spring and the lowest point in autumn as shown in TABLE 2 and FIGURE 1 (not statistically significant), and was not influenced by age or gender (p > 0.05). The delayed diagnosis term in all IBD cases was 3.1 ± 2.7 months (median: 2, range: 0–18 months). There was a minimal difference for the delay by gender as 3.0 ± 2.3 months in males (median: 2, range: 0–12 months) and 3.2 ± 3.2 months (median: 2, range: 0–18 months) in females (not significant). Of the 98 patients with CD, 51 were male (52%; TABLE 1). Appendicectomy was performed in six patients (6.1%). One patient (1%) experienced anal fistula. The seasonal CD pattern showed a peak number of cases in February, March, June and July and the lowest point in April and September (not statistically significant) (TABLE 2 & FIGURE 2). The delayed diagnosis term was 3 ± 2.8 months (median: 2.0, range: 0–18 months), with no difference between males 3.0 ± 2.7 months (median: 2.0, range: 0–10 months) and females 3.0 ± 3.0 months (median: 2.0, range: 0–18 months; not significant). There were 184 patients with CUC, of which 130 were male (71%; TABLE 1). Seasonal variation showed a peak in the number of symptomatic CUC cases in spring, and was lowest in autumn (TABLE 2 & FIGURE 3), which was found to be statistically significant (p < 0.029). The delayed diagnosis term was 3.2 ± 2.6 months (median: 2.0, range: 0–15 months) in CUC patients, with no significant difference in delay by gender. Discussion

In this study, we evaluated seasonal clustering in newly diagnosed IBD patients with clinical complaints instead of the Expert Rev. Gastroenterol. Hepatol. 9(6), (2015)

Original Research

Seasonal clustering in IBD

Table 2. Observed and expected number of cases among patients with IBD according to months of the symptom presentation. Onset of symptoms in 284 patients with IBD

Month of the year

Observed/expected/ difference in CUC (184 patients/12 = 15.3)

Observed/expected/ difference in CD (98 patients/12 = 8.2)

Observed (%)

Expected (284 patients/ 12 = 23.5)

January

23/15.3/50.3†

7/8.2/-14.6

30 (10.6%)

23.5

February

12/15.3/–21.6

11/8.2/34.2

23 (8.6%)

23.5

March



25/15.3/63.4

12/8.2/46.3

37 (13.1%)

23.5

April

23/15.3/50.3†

4/8.2/–51.2

27 (9.6%)

23.5

May

15/15.3/–2.0

7/8.2/–14.6

22 (7.8%)

23.5

June

15/15.3/–2.0

11/8.2/34.2

26 (9.2%)

23.5

July

14/15.3/–8.5

11/8.2/34.2

25 (8.9%)

23.5

August

16/15.3/4.6

7/8.2/–14.6

23 (8.2%)

23.5

September

13/15.3/–15

5/8.2/–39.0

18 (6.4%)

23.5

9/8.2/9.8

17 (6.0%)

23.5

October



8/15.3/–47.7







November

9/15.3/–41.2

6/8.2/–26.8

15 (5.3%)

23.5

December

11/15.3/–28.1

8/8.2/–2.4

19 (6.7%)

23.5

p value

p = 0.029 for only in CUC NS in CD

NS

The seasonal pattern of IBD showed a peak number of cases in early spring and the lowest point in autumn (NS). The seasonal CD pattern showed a peak number of cases in February, March, June and July and the lowest point in April and September (NS). Seasonal variation showed a peak in the number of symptomatic CUC cases in spring, and was lowest in autumn, which was found to be statistically significant (p < 0.029). Only statistical significance in the CUC group as p < 0.029. There is no statistical significance in CD group or in IBD group. † Lowest measures in the groups. ‡ Highest measures in the groups. CUC: Chronic ulcerative colitis; CD: Crohn’s diseases; IBD: Inflammatory bowel diseases; NS: Not statistically significant (p > 0.05).

endoscopic diagnosis date as used in previously published studies [19–22] . In this context, we evaluated the seasonal variability in a large IBD cohort. Another novel feature of our study was that our data were obtained from the records of gastroenterologists at our tertiary referral centers. Therefore, our study population more likely contained IBD patients with every stage of the disease. We found the number of patients affected by CUC to be the lowest in October and November (autumn) and highest in January, March and April (winter/spring). Cases with upper respiratory tract infections were observed with high frequency in the winter months of December, January and February in Turkey, and may be a relevant factor to explore. Similarly, anti-flu drugs were used relatively more often during the colder months, according to the Turkish Ministry of Health reports. In addition to upper respiratory tract infections, using these types of medications may contribute to the development of IBD in genetically susceptible individuals [18]. In contrast, enteric infections are seasonally related in Turkey, being more common during the summer months. We found the lowest peak for CUC cases in autumn, and therefore enteric infections seem less favorable as a precipitating factor for CUC onset. informahealthcare.com

60 57.4

50 40 Mean % difference

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IBD

30 27.7

20

14.9

10

10.6 6.4

0 –2.1

–10

–6.4

–2.1 –23.4

–20

–27.7

–30

–19.1

–36.2

–40 1

2

3

4

5

6 7 8 Months

9

10 11 12

Figure 1. The seasonal pattern showed a peak number of cases in early spring and the lowest point in autumn (not significant). Definition of months are as follows: 1, January; 2, February; 3, March, 4, April; 5, May; 6, June; 7, July; 8, August; 9, September; 10, October; 11, November; and 12, December. IBD: Inflammatory bowel disease.

879

Original Research

Basaranoglu, Sayilir, Demirbag, Mathew, Ala & Senturk

50

Mean % difference

34.1

34.1

25

34.1

9.8

0

–2.4 –25

–14.6

–14.6

–14.6

–26.8 –39.0 –50

–51.2 1

2

3

4

5

6 7 Months

8

9

10 11 12

Figure 2. The seasonal pattern of CD showed peaks in February, March, June and July and the lowest points in April and September (not significant). Definition of months are as follows: 1, January; 2, February; 3, March; 4, April; 5, May; 6, June; 7, July; 8, August; 9, September; 10, October; 11, November; and 12, December. CD: Crohn’s disease.

Vitamin D is essential for functioning of the immune system [19,20] and regulates both adaptive and innate immunity in human. Turkey is a relatively sunny country compared with some western European or North American cities. We can conclude that vitamin D is lowest at the end of non-sunny months,

50

47.71

40

41.18

30 Mean % difference

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46.3

20

28.10

21.57 15.03

10

8.50

1.96

0

1.96 –4.58

–10 –20 –30 –40 –50

–50.33

–60

–63.40

–50.33

–70 1

2

3

4

5

6

7

8

9

10 11 12

but highest after sunny months. Similarly, and in a close relation, adrenal corticosteroids peaks in the spring and summer months and are lowest in autumn and winter. These seasonal fluctuations in vitamin D and immune functions may explain the seasonal variations in the onset of IBD. There may also be a relation between low steroid levels in winter and early spring, and the onset of IBD. Therefore, clinical IBD symptoms may become apparent in March and April (late winter/early spring). Although blood steroid levels start to peak in spring, these high levels might not be enough to recover from disease onset in predisposed individuals, and steroid resistance may also be a factor in some patients, either secondary to genetic factors or past infection. When the individual diseases of CD and CUC were considered in our study, their seasonality outcomes were different. It should be noted that IBD is an idiopathic disease, without a single known cause. It is speculated that IBD is caused by a dysregulated immune response to host intestinal microflora, with environmental, genetic and immune factors being considered major etiological factors in IBD. There are well-established differences between UC and CD, and so seasonality may well also differ between both diseases in IBD. We also investigated the relation between seasonal cluster and gender and found no statistically significant relations. Finally, our study group presents data for the first time on the delay between symptom onset and IBD diagnosis in our cohort. There was a delay in seeking healthcare in patients with IBD (both CUC and CD), with a longer delay amongst female patients. The delay in diagnosis of IBD by 3 months in our study could be explained by socio-economic factors, levels of patient/familyeducation, as well as difficulties in reaching appropriate healthcare providers and endoscopic investigations. Performing detailed microbial investigations on our patient group may also explain this delayed diagnosis. The main limitation of this study is the relatively small number of the patients with CD, which may have been insufficient to detect seasonal variations in this group. In conclusion, we have investigated the seasonal variability of IBD and its multifactorial etiological environmental agents. We suggest the possibility that environmental exposures, such as infections, drugs or seasonal variations to vitamin D and steroid levels may trigger the onset of IBD. Our data support a seasonal pattern for the natural history of IBD, particularly in CUC. We have also identified the delay that exists in health-seeking behavior and in reaching an established IBD diagnosis. Further welldesigned and large prospective studies are required to better understand the importance of these findings presented here.

Months

Figure 3. To highlight the seasonality effect, figures’ signs are reversed (i.e., negative values are in fact positive). The number of the observed patients with CUC was the lowest in autumn and the highest in spring. Definition of months in Turkey is as follows: 1, January; 2, February; 3, March; 4, April; 5, May; 6, June; 7, July; 8, August; 9, September; 10, October; 11, November; and 12, December. CUC: Chronic ulcerative colitis.

880

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Writing assistance by Turkiye Yuksek Ihtisas Hospital was utilized in the production of this manuscript. Expert Rev. Gastroenterol. Hepatol. 9(6), (2015)

Seasonal clustering in IBD

Original Research

Key issues .

External stimuli have been considered as triggers to the onset of chronic ulcerative colitis (CUC) in genetically susceptible individuals.

.

Seasonal clustering in CUC does make sense and is timely and necessary to investigate.

.

The relation between flare of CUC and monthly clustering has been previously reported, in Western countries and the results are not in harmony.

.

There is a belief that the risk factors of CUC in the East differ from the West. Turkey is unique country lying 97% within Asia, whilst

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also sharing a border with Europe (3%). .

In this study, we evaluated seasonal clustering in newly diagnosed CUC patients with complaints.

.

While our results are not supportive of a relation between enteric infections and CUC, upper respiratory tract infections and anti-flu drugs may be linked with the onset of CUC.

.

Fluctuations of vitamin D and immune functions during the sunny and non-sunny seasons may explain the seasonal variations in the onset of CUC.

.

There was no relation between seasonal clustering, CUC and gender.

.

Delayed diagnosis has been investigated for the first time by our study group and there was a delay.

inflammatory bowel disease. Am J Gastroenterol 1994;89:847-51

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Basaranoglu M, Demirkok SS, Coker E. Considerations in seasonal variation studies in IBD and re-evaluation of Aratari et al. seasonality results. Dig Liver Dis 2006;38: 710-11

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Seasonal clustering in inflammatory bowel disease: a single centre experience.

External stimuli are considered as possible triggers for the onset of inflammatory bowel disease (IBD), and particularly chronic ulcerative colitis (C...
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