- Email: [email protected]
Predictors for Pouchitis After Ileal Pouch-Anal Anastomosis for Pediatric-Onset Ulcerative Colitis
j o u r n a l o f s u r g i c a l r e s e a r c h j u n e 2 0 1 9 ( 2 3 8 ) 7 2 e7 8
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Predictors for Pouchitis After Ileal Pouch-Anal Anastomosis for Pediatric-Onset Ulcerative Colitis Yuhki Koike, MD, PhD,* Keiichi Uchida, MD, PhD,* Mikihiro Inoue, MD, PhD, Kohei Matsushita, MD, PhD, Yoshiki Okita, MD, PhD, Yuji Toiyama, MD, PhD, Toshimitsu Araki, MD, PhD, and Masato Kusunoki, MD, PhD Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
article info
abstract
Article history:
Background: The predictive factors for the development of pouchitis after ileal pouch-anal
Received 8 August 2018
anastomosis (IPAA) in pediatric-onset ulcerative colitis (UC) have not been well investi-
Received in revised form
gated. The present study aimed to determine the predictive factors for the development of
25 October 2018
pouchitis after IPAA in the pediatric UC population.
Accepted 8 January 2019
Methods: The data from 54 patients with pediatric-onset UC who underwent IPAA in Mie
Available online xxx
University Hospital between 2000 and 2017 were retrospectively reviewed. A modified
Keywords:
intraoperative, and postoperative predictors for pouchitis including various demographic
pouchitis disease activity index of 5 was defined as pouchitis. Potential preoperative, Ulcerative colitis
and clinical variables were analyzed using Cox regression analysis, Students’ t-tests, Mann
Pouchitis
eWhitney U tests, and KaplaneMeier curves. The optimal cutoff value for continuous
Pediatric
variables was determined using the receiver operating characteristic curve analysis.
Risk factor
Results: Pouchitis was identified in 17 (31.5%) patients within 5 y of follow-up. In multivariable analysis, the independent predictors for pouchitis were preoperative cumulative steroid dose of >10,000 mg (P ¼ 0.0056) and >65% neutrophils just before IPAA (P ¼ 0.032). Multivariate analysis revealed that the independent predictors of pouchitis were a total steroid dose of >10,000 mg (P ¼ 0.0002) and a neutrophil percentage of >65% (P ¼ 0.0078). No patient for whom both of these independent predictors were negative developed pouchitis, whereas >40% of patients who had one or both predictors developed pouchitis. Conclusions: In pediatric patients with UC, the predictive factors for pouchitis development are a greater cumulative total dose of steroids and a greater percentage of neutrophils before IPAA. ª 2019 Elsevier Inc. All rights reserved.
Introduction Current surgical procedures enable children with ulcerative colitis (UC) to achieve an excellent quality of life (QOL) with
intestinal continuity and without permanent ileostomy. However, there remains a substantial risk of pouchitis after ileal pouch-anal anastomosis (IPAA), and pouchitis is one of the major factors that reduces postoperative QOL in patients
* Corresponding authors. Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Edobashi 2174, Tsu, Mie 514-8507, Japan. Tel.: þ81 59 232 1111x5645; fax: þ81 59 232 6968. E-mail address: [email protected] (Y. Koike). 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.01.022
koike et al predictors for pediatric pouchitis
with UC.1,2 The reported cumulative frequencies of pouchitis development 10-11 y after IPAA are 23%-46%, and approximately 50% of patients with UC who undergo IPAA develop at least one episode of pouchitis.3-5 Several studies have reported that the incidence of pouchitis in children undergoing IPAA varies from 19% to 73%.6-9 Postoperative pouchitis might be the main reason that pediatric patients with UC are reluctant to go to school after IPAA. Therefore, it is important to predict which post-IPAA patients are likely to develop pouchitis. This prediction will alert the attending physician to the post-IPAA patients who should be more closely monitored and rapidly started on preventive and therapeutic treatment of pouchitis to maintain QOL. As the etiology of pouchitis remains unclear, it is difficult to instigate preventative strategies and management of this complication. Several reports have identified the risk factors of pouchitis as younger age at the time of UC onset, expansive colonic disease, extraintestinal manifestation, positivity for perinuclear antineutrophil cytoplasmic antibody preoperatively, preoperative steroid use, and the presence of interleukin-1 receptor antagonist gene allele 2.10-20 Although intraoperative and postoperative clinical factors might influence the pathogenesis of pouchitis development, no study has included intraoperative and postoperative clinical factors as well as preoperative factors in the analysis to identify the predictive factors of pouchitis. Moreover, these previous studies that have focused on pediatric patients are limited and include small sample sizes. The present study is the first to evaluate the independent influences of preoperative, intraoperative, and postoperative predictive factors for pediatric pouchitis after IPAA.
Materials and methods Study population Patients with UC who underwent IPAA at Mie University Hospital between January 2000 and December 2017 were included. Patients under the UC onset age of 15 y were included in the study. Fifty-four consecutive patients undergoing IPAA who had completed available data set at our institution were followed for this study period. The Institutional Review Board of Mie University Hospital approved the present study (IRB number: 1608). Informed consent was obtained from the guardians of all patients, and in case of the patients aged 7-14 y or patients who had enough ability to understand the study, informed assent was also obtained from the patients themselves. In general, postoperative UC patients were attended to our hospital at 3 mo intervals for the first postoperative year and every 6 mo intervals or out of necessity after the second postoperative year.
73
with subtotal colectomy with ileostomy construction and sigmoid mucous fistula formation in the first stage, and then remnant proctocolectomy and ileoanal anastomosis with reconstruction of the ileostomy are performed in the second stage, and finishes at ileostomy closure in the third stage. Which operation type (a two- or three-staged operation) should be selected depends on the patient’s preoperative condition, such as existence of massive anal bleeding/vital signs/anemia/nutritional status/age/sepsis/preoperative steroid use etc.21
Diagnosis of pouchitis The diagnosis of pouchitis was performed using a combination of clinical symptoms and endoscopic examination. A modified Pouchitis Disease Activity Index (mPDAI) score of 5 points was used for the definition of pouchitis in this study.22,23 Causes of secondary pouchitis (e.g., anastomotic stricture, pelvic sepsis, pouch ischemia, Clostridium difficile infection, cytomegalovirus infection, or regular use of nonsteroidal anti-inflammatory drugs) were excluded before diagnosing pouchitis. A mPDAI score of 4 points was defined as negative condition of pouchitis. Generally, oral metronidazole or ciprofloxacin for 2 wk were prescribed for the treatment of pouchitis. The duration between stoma closure after IPAA surgery and the first occurrence of pouchitis was recorded.
Definition and assessment of clinical variables The general variables evaluated as potential predictive factors for pouchitis were age at UC onset, age at surgery, sex, Pediatric Ulcerative Colitis Activity Index (PUCAI), disease duration, extent of colitis, body mass index, extraintestinal manifestations, pouchitis-free survival (days), cumulative dose of steroids before colectomy, antietumor necrosis factoralpha antibody use, immunomodulator use, and preoperative anal resting and anal squeezing pressures. The intraoperative variables evaluated as potential predictors of pouchitis were type of operation (two- or three-stage), type of IPAA surgery (laparoscopic or open), operation time, and blood loss. The postoperative variables evaluated as potential predictors of pouchitis were surgical site infection, defecation frequency (after stoma closure), number of episodes of soiling per week after stoma closure, and postoperative anal resting and anal squeezing pressures. Postoperative soiling was recorded within 1 to 3 mo after the stoma closure operation (restoration of gastrointestinal continuity). Extraintestinal manifestations included joints, skin, eyes, and any organ system such as arthritis, primary sclerosing cholangitis, uveitis, and pyoderma gangrenosum manifestations. The calculation of the estimated cumulative dose of steroids was based on the dose of converted prednisolone since the initial UC diagnosis.
Statistical analysis Selection of staged surgery for pediatric ulcerative colitis In our facility, we usually perform more than two staged surgeries for pediatric UC. The two-staged operation starts with total proctocolectomy and ileoanal anastomosis with a diversion ileostomy construction in the first stage, and end with ileostomy closure in the second stage. The three-staged operation starts
Data were analyzed using JMP version 5 (SAS Institute, Inc, Cary, NC). Continuous variables are expressed as the median interquartile range. Differences between groups were analyzed using the ManneWhitney U test as appropriate, based on the non-normal distribution of each valuable observed using F tests. Categorical variables were compared
74
j o u r n a l o f s u r g i c a l r e s e a r c h j u n e 2 0 1 9 ( 2 3 8 ) 7 2 e7 8
using the chi-squared method or Fisher’s exact test if the expected cell counts were less than 5. The KaplaneMeier method was used for the estimation of the cumulative incidence of pouchitis. The calculation of the pouchitis-free survival period was defined between the date of restoration of gastrointestinal continuity and the date when antibiotic therapy for pouchitis was started, and the date of the last patients’ follow-up were censored. The Cox proportional hazard regression model was used to evaluate the perioperative predictive factors of pouchitis. The cutoff values for continuous variables with a P < 0.05 in the univariate analysis were determined based on receiver operating characteristic analysis for the occurrence of pouchitis, and their cutoff values were used in the multivariate analysis.
Table 1 e Patient characteristics. Clinical variables General Sex (male/female)
11.0 5.25
Disease duration, y (median IQR)
3.00 4.68
Age at operation, y (median IQR)
14.4 5.23
Extent of colitis (left side/total)
6/48
Extraintestinal manifestations
3
BMI (median IQR)
Pouchitis within 5 y after IPAA (þ/) Pouchitis-free survival, d (median IQR) Total dose of steroids (median IQR)
Patient characteristics A total of 54 patients underwent IPAA with mucosectomy during a median follow-up duration of 9.0 (range 1-17) y (Table 1). Among these 54 patients, the median age at UC onset was 11.0 5.25 y, and the median age at IPAA surgery was 14.4 5.23 (range 3.5-21) y. Of the 54 patients, 17 (31.5%) developed pouchitis within 5 y after IPAA. The median duration from restoration of gastrointestinal continuity to the occurrence of pouchitis was 576 999 d. Both anal resting pressure and squeezing pressure tended to be lower postoperatively than preoperatively; however, these changes were not statistically significant. Compared with open IPAA surgery, laparoscopic IPAA surgery took a significantly longer operation time (271.6 63.6 min versus 406 97.0, P ¼ 0.0002) and had lesser operative blood loss (322 407 mL versus 141 146 mL, P ¼ 0.06).
Predictive factors of pouchitis Table 2 showed the results of univariate analysis for predictive factors of the development of overall pouchitis. Univariate analysis demonstrated that total dose of steroids (P ¼ 0.0056), postoperative soiling symptoms (P ¼ 0.037), and neutrophil percentage just before colectomy (P ¼ 0.032) were the significant predictive factors for overall pouchitis. Of these three potential predictive factors for pouchitis development, total dose of steroids and neutrophil percentage were included in the receiver operating characteristic analysis for the occurrence of pouchitis to set the best cutoff values. The cutoff value for the total steroid dose was >10,000 mg before IPAA surgery, and that for neutrophil percentage was >65%. Multivariate analysis was then performed using the three categorized variables (total dose of steroids [10,000 mg or >10,000 mg], postoperative soiling [ or þ], neutrophil percentage [65% or >65%]). Multivariate analysis revealed that the factors independently associated with the development of pouchitis after IPAA were total dose of steroids (P ¼ 0.0002) and neutrophil percentage (P ¼ 0.0078, Table 3). In particular, the highest odds ratio for total steroid dose was 18.5, revealing that reducing the total dose of steroids before IPAA could have a potential protective effect in the development of pouchitis.
33/21
Age at onset of ulcerative colitis, y (median IQR)
PUCAI score at IPAA surgery (median IQR)
Results
All patients (n ¼ 54)
17.2 5.34 33.79 16.8 17/37 576 999 6350 10,512
Immunomodulator Yes/No
40/14
AntieTNF-a antibody therapy Yes/No
10/44
Preoperative anal resting pressure (median IQR)
57.5 38.7
Preoperative anal squeezing pressure (median IQR)
130 92.6
Intraoperative Type of operation Two-stage
36
Three-stage
18
Laparoscopic IPAA surgery Yes/No
11/43
Operation time at IPAA, minute (median IQR)
285 116
Operative blood loss during IPAA, mL (median IQR)
196 256
Blood transfusion Yes/No
8/46
Postoperative Surgical site infection, n (%) Postoperative anal resting pressure (median IQR) Postoperative anal squeezing pressure (median IQR)
13 (24.1%) 30.8 30.2 89 82.5
BMI ¼ body mass index; IQR ¼ interquartile range; PUCAI ¼ pediatric ulcerative colitis activity index; TNF ¼ tumor necrosis factor.
Cumulative incidence of pouchitis development Figure showed the result of the KaplaneMeier analysis divided by the relationship between the cumulative incidence of pouchitis development and the number of predictive factors (total dose of steroids >10,000 mg and neutrophil percentage >65%). The incidence of pouchitis in patients with two predictive factors (n ¼ 13) was significantly greater than that in patients with one (n ¼ 23, P ¼ 0.021) or no predictive factors (n ¼ 18, P < 0.001). The incidence of pouchitis was also
75
koike et al predictors for pediatric pouchitis
Table 2 e Univariate analysis of the potential predictors of pouchitis. Variables
Pouchitis () (n ¼ 37)
Pouchitis (þ) (n ¼ 17)
21/16
12/5
0.33
6/31
3/14
0.89
27/10
8/9
0.064
25/12
8/9
0.15
3/34
3/14
0.3
P value
General Sex Male/Female Age at onset of ulcerative colitis (y) 6/>6 Disease duration (y) 5/>5 Age at operation (y) 15/>15 Extent of colitis Left side/Total Extraintestinal manifestations Yes/No Body mass index
2/35
1/16
18.4 3.92
17.6 3.21
0.94 0.53
PUCAI score
34.59 2.80
32.05 4.09
Total dose of steroids
6794 7421
12,884 6084
25/12
15/2
0.11
6/31
4/13
0.52
0.62 0.0056
Immunomodulator Yes/No AntieTNF-a antibody therapy Yes/No Preoperative anal resting pressure
63.7 33.2
57.1 24.8
0.78
Preoperative anal squeezing pressure
147 78.9
129 54.1
0.88
Number of operation stages Two-staged/Three-staged
22/15
14/3
0.087
Type of operation Open/Laparoscopic
31/6
12/5
0.26
Operation time (min)
314 125
290 71.1
0.93
Operative blood loss (mL)
333 435
184 155
0.18
Blood transfusion Yes/No
7/30
1/16
0.21
8/29
5/12
0.53
8/9
0.037
Surgical site infection Yes/No Soiling Yes/No
7/29
Postoperative anal resting pressure
38.8 20.8
38.7 17.4
0.82
Postoperative anal squeezing pressure
100 73.4
126 77.2
0.25
WBC Count (/mm3)
9709 787
10,272 828
Neutrophil %
65.7 13.6
73.4 8.7
0.032
Hemoglobin
10.7 2.58
11.4 2.43
0.26
CRP (mg/dL)
1.27 0.29
1.54 0.84
0.56
Albumin (g/dL)
3.62 0.11
3.97 0.15
0.058
Cholinesterase (IU)
0.69 0.05
0.87 0.07
0.068
Laboratory data just before colectomy 0.25
WBC ¼ white blood cell; CRP ¼ C-reactive protein; PUCAI ¼ pediatric ulcerative colitis activity index; TNF ¼ tumor necrosis factor. The bold word meant that P value was under 0.05 (P < 0.05).
significantly greater in patients with one predictive factor compared with those with no predictive factors (P ¼ 0.043). Moreover, there was no occurrence of pouchitis in the group of patients with a score of 0 (neither of the two predictive factors).
Discussion The present study is the first study to evaluate the predictive factors for the development of pouchitis in pediatric UC that
76
j o u r n a l o f s u r g i c a l r e s e a r c h j u n e 2 0 1 9 ( 2 3 8 ) 7 2 e7 8
Table 3 e Multivariate analysis of the potential predictors of pouchitis. Variables
Odds ratio
95% CI
P value
Total dose of steroids (10,000 or >10,000)
18.5
3.75-13.0
0.0002
Postoperative soiling ( or þ) Neutrophil % (65% or >65%)
3.21 12.4
0.52-2.38
0.21
1.84-15.0
0.0078
CI ¼ confidence intervals. The bold word meant that P value was under 0.05 (P < 0.05).
has analyzed intraoperative and postoperative clinical features as well as preoperative features. The main findings of our study were that multivariate analysis identified total dose of steroids and preoperative neutrophil percentage before IPAA as independent risk factors for the subsequent development of pouchitis after IPAA. We focused on the analysis of the risk factors for the cumulative pouchitis incidence, without categorization between cumulative and chronic pouchitis incidences, while several previous studies focused on the risk factor analysis for both pouchitis types.10,13,15,18,24,25 We focused on the cumulative pouchitis incidence because identification of the risk factors for the cumulative pouchitis incidence is important in preventing or reducing the development of pouchitis, and also because the cumulative pouchitis incidence always includes the chronic pouchitis occurrence. Hence, the present results may provide useful information for the prevention of both acute and chronic pouchitis after IPAA in pediatric patients with UC. In the present study, a cumulative overdose of steroids (>10,000 mg) was an independent risk factor for pouchitis in patients with pediatric-onset UC. Preoperative steroid use has been also reported as a risk factor for the development of pouchitis.10,11,15 Fleshner et al.15 reported that the steroid administration before colectomy was associated with the development of acute pouchitis. They also demonstrated that although aggressive UC condition before the operation may be
Fig e The relationship between the cumulative incidence of pouchitis over time and the number of predictive factors present in each case. Patients with two predictive factors (score: 2) had a significantly greater incidence of pouchitis than patients with one (score: 1) or no predictive factors (score: 0). P < 0.001 for score 2 versus score 0; P [ 0.021 for score 2 versusu score 1.
a risk for pouchitis postoperatively, this trend was not seen in patients with other immunosuppressive drugs before IPAA.15 The present study also revealed that the use of immunomodulator was not a risk factor for pouchitis development. Considering these results together, when clinicians treat pediatric UC patients, switching the steroid to other immunosuppressive agents may be a better option if possible. Kalkan et al.11 also reported that a more severe preoperative clinical course and steroid dependency may be a preoperative predictors for the development of pouchitis. They suggested that aggressive disease condition during the preoperative period may be a risk factor for the development of pouchitis.11 In the present study, the total dose of steroids was a significant risk factor for pouchitis, whereas the PUCAI was not a risk factor. To check the relationship between the PUCAI and the total dose of steroids, we conducted the additional analysis between PUCAI and total steroid dose. Patients with >10,000 mg steroid were the mean 22.25 point of PUCAI, on the other hand, patient with 10,000 mg were the mean 31.12 point of PUCAI. These data indicated that patients with >10,000 mg steroid were not always in the condition of aggressive disease phenotypes. In our facility, the PUCAI score was relatively low at the time of colectomy or IPAA because we usually select the three-staged operation for pediatric patients with severe UC to reduce the occurrence of postoperative complications and also because we sometimes select the best operation timing of IPAA when preoperative inflammatory condition is lower than the admission point. In the 54 patients studied, four patients had the history of steroid pulse therapy preoperatively. Two of the four patients had developed the pouchitis (50% pouchitis rate). Unfortunately, however, we could not reveal why high amount of steroid dose was the risk factor for development of pouchitis in this study; these data also supports the relationship between the preoperative high amount of steroid dose and pouchitis development. Regarding the total dose of steroids, our patients had relatively high cumulative doses of steroids before IPAA (Table 1). In Japan, patients with intractable UC are generally treated conservatively, even when minor steroid side effects are present.26 This trend might be stronger in pediatric patients with UC compared with adults with UC, as both the physicians and the patients’ parents tend to avoid surgical treatment due to considerations of the patient’s future life. As the present results and previous reports show that steroid use is a risk factor for pouchitis, pediatric patients with UC who are being effectively treated by primary steroid administration but then experience UC relapse and need to use steroids continuously or repeatedly should be treated by IPAA surgery before their total cumulative dose of steroids becomes too high, as this may reduce the potential risk of pouchitis. The present study is the first to identify a neutrophil percentage of >65% before IPAA surgery as one of the potential risk factors for pouchitis. Yoshiyama et al.27 reported that steroid-overdosed UC patients may have a functional deficit in neutrophils (e.g., high neutrophil necrosis rate, increased release of proinflammatory cytokines, and increased release of proteolytic enzymes). In their study, UC patients were divided into two groups according to their total preoperative dosage of prednisolone (>10,000 mg, 10,000 mg). These data support our study, moreover, would be one of the possible
koike et al predictors for pediatric pouchitis
reason why high percentage of neutrophil is one of the risk factor for the development of pouchitis. In the present univariate analysis, postoperative presence of soiling symptoms (1-7 times/wk) was a significant risk factor for pouchitis, although it was not an independent risk factor for pouchitis in the multivariate analysis. The association between postoperative soiling symptoms and pouchitis development has not been previously reported, as no previous report has included the postoperative clinical features (such as soiling, and postoperative anal resting, and squeezing pressures) in the analysis of the risk factors for pouchitis. The reason for the relationship between postoperative soiling and the development of pouchitis is unclear. This symptom of soiling might affect the microbiome flora in the pouch, and further prospective analysis such as detailed classification of the microbiome in the pouch might reveal the mechanism between soiling symptoms and pouchitis development. The limitations of the present study relate to its retrospective nature and the small sample size; however, the present study included the largest sample size compared with previous studies on pediatric UC.24,25 Diagnosing pouchitis using the mPDAI may also cause diagnostic bias. Moreover, the present study included the perioperative and postoperative clinical features in the risk analysis of pouchitis, whereas the previously reported studies have not included these clinical factors; hence, it might be difficult to compare our results with previous reports that analyzed the predictive factors for pouchitis development after IPAA. Finally, the present study was unable to analyze the fecal microbiome characteristics because of its retrospective nature; a prospective analysis may help determine whether these are risk factors for pouchitis development.
Conclusion Patients with pediatric-onset UC who receive a greater cumulative dose of steroids before IPAA and those who have a greater percentage of neutrophils just before IPAA surgery may have a relatively high risk for the development of pouchitis. Although the association between these two predictive factors and a greater incidence of pouchitis remains unclear, further studies may provide novel information on the etiology of pouchitis. Using the predictive factors for pouchitis may enable us to determine which pediatric patients with UC who undergo IPAA are at high risk of developing pouchitis, give patients detailed information regarding postoperative complications (especially pouchitis), and provide an enhanced prophylaxis or treatment plan in patients with the greatest pouchitis risk.
Acknowledgment The authors thank Kelly Zammit, BVSc, from Edanz Group (www.edanzediting.com/ac), for editing a draft of this article. Authors’ contributions: Conception or design of the work was contributed by Y.K. and K.U. Data collection was carried out by Y.K., K.M., M.I., and Y.O. Data analysis was performed
77
by T.A. and M.K. Interpretation of data for the work was done by Y.T. and M.K. Manuscript was written by Y.K.
Disclosure All authors declare no conflicts of interest for this article.
references
1. Shen B, Fazio VW, Remzi FH, et al. Comprehensive evaluation of inflammatory and noninflammatory sequelae of ileal pouch-anal anastomoses. Am J Gastroenterol. 2005;100:93e101. 2. Coffey JC, Winter DC, Neary P, et al. Quality of life after ileal pouch-anal anastomosis: an evaluation of diet and other factors using the Cleveland global quality of life instrument. Dis Colon Rectum. 2002;45:30e38. 3. Shen B. Acute and chronic pouchitis–pathogenesis, diagnosis and treatment. Nat Rev Gastroenterol Hepatol. 2012;9:323e333. 4. Ferrante M, Declerck S, Coopmans T, et al. Development of pouchitis following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis: a role for serological markers and microbial pattern recognition receptor genes. J Crohns Colitis. 2008;2:142e151. 5. Fazio VW, Ziv Y, Church JM, et al. Ileal pouch-anal anastomoses complications and function in 1005 patients. Ann Surg. 1995;222:120e127. 6. Wewer V, Hesselfeldt P, Qvist N, et al. J-pouch ileoanal anastomosis in children and adolescents with ulcerative colitis: functional outcome, satisfaction and impact on social life. J Pediatr Gastroenterol Nutr. 2005;40:189e193. 7. Chew SS, Kerdic RI, Yang JL, et al. Functional outcome and quality of life after ileal pouch-anal anastomosis in children and adults. ANZ J Surg. 2003;73:983e987. 8. Alexander F, Sarigol S, DiFiore J, et al. Fate of the pouch in 151 pediatric patients after ileal pouch anal anastomosis. J Pediatr Surg. 2003;38:78e82. 9. Sarigol S, Wyllie R, Gramlich T, et al. Incidence of dysplasia in pelvic pouches in pediatric patients after ileal pouch-anal anastomosis for ulcerative colitis. J Pediatr Gastroenterol Nutr. 1999;28:429e434. 10. Okita Y, Araki T, Tanaka K, et al. Predictive factors for development of chronic pouchitis after ileal pouch-anal anastomosis in ulcerative colitis. Digestion. 2013;88:101e109. 11. Kalkan IH, Dagli U, Onder FO, et al. Evaluation of preoperative predictors of development of pouchitis after ileal-pouchanastomosis in ulcerative colitis. Clin Res Hepatol Gastroenterol. 2012;36:622e627. 12. Pardi DS, D’Haens G, Shen B, et al. Clinical guidelines for the management of pouchitis. Inflamm Bowel Dis. 2009;15:1424e1431. 13. Hoda KM, Collins JF, Knigge KL, et al. Predictors of pouchitis after ileal pouch-anal anastomosis: a retrospective review. Dis Colon Rectum. 2008;51:554e560. 14. Fleshner P, Ippoliti A, Dubinsky M, et al. Both preoperative perinuclear antineutrophil cytoplasmic antibody and antiCBir1 expression in ulcerative colitis patients influence pouchitis development after ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol. 2008;6:561e568. 15. Fleshner P, Ippoliti A, Dubinsky M, et al. A prospective multivariate analysis of clinical factors associated with pouchitis after ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol. 2007;5:952e958. quiz 887. 16. Meier CB, Hegazi RA, Aisenberg J, et al. Innate immune receptor genetic polymorphisms in pouchitis: is CARD15 a susceptibility factor? Inflamm Bowel Dis. 2005;11:965e971.
78
j o u r n a l o f s u r g i c a l r e s e a r c h j u n e 2 0 1 9 ( 2 3 8 ) 7 2 e7 8
17. Achkar JP, Al-Haddad M, Lashner B, et al. Differentiating risk factors for acute and chronic pouchitis. Clin Gastroenterol Hepatol. 2005;3:60e66. 18. Hata K, Watanabe T, Shinozaki M, et al. Patients with extraintestinal manifestations have a higher risk of developing pouchitis in ulcerative colitis: multivariate analysis. Scand J Gastroenterol. 2003;38:1055e1058. 19. Fleshner PR, Vasiliauskas EA, Kam LY, et al. High level perinuclear antineutrophil cytoplasmic antibody (pANCA) in ulcerative colitis patients before colectomy predicts the development of chronic pouchitis after ileal pouch-anal anastomosis. Gut. 2001;49:671e677. 20. Carter MJ, Di Giovine FS, Cox A, et al. The interleukin 1 receptor antagonist gene allele 2 as a predictor of pouchitis following colectomy and IPAA in ulcerative colitis. Gastroenterology. 2001;121:805e811. 21. Uchida K, Araki T, Kusunoki M. History of and current issues affecting surgery for pediatric ulcerative colitis. Surg Today. 2013;43:1219e1231.
22. Shen B, Achkar JP, Connor JT, et al. Modified pouchitis disease activity index: a simplified approach to the diagnosis of pouchitis. Dis Colon Rectum. 2003;46:748e753. 23. Shen B. Pouchitis: what every gastroenterologist needs to know. Clin Gastroenterol Hepatol. 2013;11:1538e1549. 24. Rinawi F, Assa A, Eliakim R, et al. Predictors of pouchitis after ileal pouch-anal anastomosis in pediatric-onset ulcerative colitis. Eur J Gastroenterol Hepatol. 2017;29:1079e1085. 25. Dharmaraj R, Dasgupta M, Simpson P, et al. Predictors of pouchitis after ileal pouch-anal anastomosis in children. J Pediatr Gastroenterol Nutr. 2016;63:e58ee62. 26. Shinozaki M, Suzuki K, Sawada T, et al. Steroid complications and surgery in intractable ulcerative colitis. J Gastroenterol. 1998;33:196e200. 27. Yoshiyama S, Miki C, Okita Y, et al. Neutrophil-related immunoinflammatory disturbance in steroid-overdosed ulcerative colitis patients. J Gastroenterol. 2008;43: 789e797.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Predictors for Pouchitis After Ileal Pouch-Anal Anastomosis for Pediatric-Onset Ulcerative Colitis Yuhki Koike, MD, PhD,* Keiichi Uchida, MD, PhD,* Mikihiro Inoue, MD, PhD, Kohei Matsushita, MD, PhD, Yoshiki Okita, MD, PhD, Yuji Toiyama, MD, PhD, Toshimitsu Araki, MD, PhD, and Masato Kusunoki, MD, PhD Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
article info
abstract
Article history:
Background: The predictive factors for the development of pouchitis after ileal pouch-anal
Received 8 August 2018
anastomosis (IPAA) in pediatric-onset ulcerative colitis (UC) have not been well investi-
Received in revised form
gated. The present study aimed to determine the predictive factors for the development of
25 October 2018
pouchitis after IPAA in the pediatric UC population.
Accepted 8 January 2019
Methods: The data from 54 patients with pediatric-onset UC who underwent IPAA in Mie
Available online xxx
University Hospital between 2000 and 2017 were retrospectively reviewed. A modified
Keywords:
intraoperative, and postoperative predictors for pouchitis including various demographic
pouchitis disease activity index of 5 was defined as pouchitis. Potential preoperative, Ulcerative colitis
and clinical variables were analyzed using Cox regression analysis, Students’ t-tests, Mann
Pouchitis
eWhitney U tests, and KaplaneMeier curves. The optimal cutoff value for continuous
Pediatric
variables was determined using the receiver operating characteristic curve analysis.
Risk factor
Results: Pouchitis was identified in 17 (31.5%) patients within 5 y of follow-up. In multivariable analysis, the independent predictors for pouchitis were preoperative cumulative steroid dose of >10,000 mg (P ¼ 0.0056) and >65% neutrophils just before IPAA (P ¼ 0.032). Multivariate analysis revealed that the independent predictors of pouchitis were a total steroid dose of >10,000 mg (P ¼ 0.0002) and a neutrophil percentage of >65% (P ¼ 0.0078). No patient for whom both of these independent predictors were negative developed pouchitis, whereas >40% of patients who had one or both predictors developed pouchitis. Conclusions: In pediatric patients with UC, the predictive factors for pouchitis development are a greater cumulative total dose of steroids and a greater percentage of neutrophils before IPAA. ª 2019 Elsevier Inc. All rights reserved.
Introduction Current surgical procedures enable children with ulcerative colitis (UC) to achieve an excellent quality of life (QOL) with
intestinal continuity and without permanent ileostomy. However, there remains a substantial risk of pouchitis after ileal pouch-anal anastomosis (IPAA), and pouchitis is one of the major factors that reduces postoperative QOL in patients
* Corresponding authors. Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Edobashi 2174, Tsu, Mie 514-8507, Japan. Tel.: þ81 59 232 1111x5645; fax: þ81 59 232 6968. E-mail address: [email protected] (Y. Koike). 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.01.022
koike et al predictors for pediatric pouchitis
with UC.1,2 The reported cumulative frequencies of pouchitis development 10-11 y after IPAA are 23%-46%, and approximately 50% of patients with UC who undergo IPAA develop at least one episode of pouchitis.3-5 Several studies have reported that the incidence of pouchitis in children undergoing IPAA varies from 19% to 73%.6-9 Postoperative pouchitis might be the main reason that pediatric patients with UC are reluctant to go to school after IPAA. Therefore, it is important to predict which post-IPAA patients are likely to develop pouchitis. This prediction will alert the attending physician to the post-IPAA patients who should be more closely monitored and rapidly started on preventive and therapeutic treatment of pouchitis to maintain QOL. As the etiology of pouchitis remains unclear, it is difficult to instigate preventative strategies and management of this complication. Several reports have identified the risk factors of pouchitis as younger age at the time of UC onset, expansive colonic disease, extraintestinal manifestation, positivity for perinuclear antineutrophil cytoplasmic antibody preoperatively, preoperative steroid use, and the presence of interleukin-1 receptor antagonist gene allele 2.10-20 Although intraoperative and postoperative clinical factors might influence the pathogenesis of pouchitis development, no study has included intraoperative and postoperative clinical factors as well as preoperative factors in the analysis to identify the predictive factors of pouchitis. Moreover, these previous studies that have focused on pediatric patients are limited and include small sample sizes. The present study is the first to evaluate the independent influences of preoperative, intraoperative, and postoperative predictive factors for pediatric pouchitis after IPAA.
Materials and methods Study population Patients with UC who underwent IPAA at Mie University Hospital between January 2000 and December 2017 were included. Patients under the UC onset age of 15 y were included in the study. Fifty-four consecutive patients undergoing IPAA who had completed available data set at our institution were followed for this study period. The Institutional Review Board of Mie University Hospital approved the present study (IRB number: 1608). Informed consent was obtained from the guardians of all patients, and in case of the patients aged 7-14 y or patients who had enough ability to understand the study, informed assent was also obtained from the patients themselves. In general, postoperative UC patients were attended to our hospital at 3 mo intervals for the first postoperative year and every 6 mo intervals or out of necessity after the second postoperative year.
73
with subtotal colectomy with ileostomy construction and sigmoid mucous fistula formation in the first stage, and then remnant proctocolectomy and ileoanal anastomosis with reconstruction of the ileostomy are performed in the second stage, and finishes at ileostomy closure in the third stage. Which operation type (a two- or three-staged operation) should be selected depends on the patient’s preoperative condition, such as existence of massive anal bleeding/vital signs/anemia/nutritional status/age/sepsis/preoperative steroid use etc.21
Diagnosis of pouchitis The diagnosis of pouchitis was performed using a combination of clinical symptoms and endoscopic examination. A modified Pouchitis Disease Activity Index (mPDAI) score of 5 points was used for the definition of pouchitis in this study.22,23 Causes of secondary pouchitis (e.g., anastomotic stricture, pelvic sepsis, pouch ischemia, Clostridium difficile infection, cytomegalovirus infection, or regular use of nonsteroidal anti-inflammatory drugs) were excluded before diagnosing pouchitis. A mPDAI score of 4 points was defined as negative condition of pouchitis. Generally, oral metronidazole or ciprofloxacin for 2 wk were prescribed for the treatment of pouchitis. The duration between stoma closure after IPAA surgery and the first occurrence of pouchitis was recorded.
Definition and assessment of clinical variables The general variables evaluated as potential predictive factors for pouchitis were age at UC onset, age at surgery, sex, Pediatric Ulcerative Colitis Activity Index (PUCAI), disease duration, extent of colitis, body mass index, extraintestinal manifestations, pouchitis-free survival (days), cumulative dose of steroids before colectomy, antietumor necrosis factoralpha antibody use, immunomodulator use, and preoperative anal resting and anal squeezing pressures. The intraoperative variables evaluated as potential predictors of pouchitis were type of operation (two- or three-stage), type of IPAA surgery (laparoscopic or open), operation time, and blood loss. The postoperative variables evaluated as potential predictors of pouchitis were surgical site infection, defecation frequency (after stoma closure), number of episodes of soiling per week after stoma closure, and postoperative anal resting and anal squeezing pressures. Postoperative soiling was recorded within 1 to 3 mo after the stoma closure operation (restoration of gastrointestinal continuity). Extraintestinal manifestations included joints, skin, eyes, and any organ system such as arthritis, primary sclerosing cholangitis, uveitis, and pyoderma gangrenosum manifestations. The calculation of the estimated cumulative dose of steroids was based on the dose of converted prednisolone since the initial UC diagnosis.
Statistical analysis Selection of staged surgery for pediatric ulcerative colitis In our facility, we usually perform more than two staged surgeries for pediatric UC. The two-staged operation starts with total proctocolectomy and ileoanal anastomosis with a diversion ileostomy construction in the first stage, and end with ileostomy closure in the second stage. The three-staged operation starts
Data were analyzed using JMP version 5 (SAS Institute, Inc, Cary, NC). Continuous variables are expressed as the median interquartile range. Differences between groups were analyzed using the ManneWhitney U test as appropriate, based on the non-normal distribution of each valuable observed using F tests. Categorical variables were compared
74
j o u r n a l o f s u r g i c a l r e s e a r c h j u n e 2 0 1 9 ( 2 3 8 ) 7 2 e7 8
using the chi-squared method or Fisher’s exact test if the expected cell counts were less than 5. The KaplaneMeier method was used for the estimation of the cumulative incidence of pouchitis. The calculation of the pouchitis-free survival period was defined between the date of restoration of gastrointestinal continuity and the date when antibiotic therapy for pouchitis was started, and the date of the last patients’ follow-up were censored. The Cox proportional hazard regression model was used to evaluate the perioperative predictive factors of pouchitis. The cutoff values for continuous variables with a P < 0.05 in the univariate analysis were determined based on receiver operating characteristic analysis for the occurrence of pouchitis, and their cutoff values were used in the multivariate analysis.
Table 1 e Patient characteristics. Clinical variables General Sex (male/female)
11.0 5.25
Disease duration, y (median IQR)
3.00 4.68
Age at operation, y (median IQR)
14.4 5.23
Extent of colitis (left side/total)
6/48
Extraintestinal manifestations
3
BMI (median IQR)
Pouchitis within 5 y after IPAA (þ/) Pouchitis-free survival, d (median IQR) Total dose of steroids (median IQR)
Patient characteristics A total of 54 patients underwent IPAA with mucosectomy during a median follow-up duration of 9.0 (range 1-17) y (Table 1). Among these 54 patients, the median age at UC onset was 11.0 5.25 y, and the median age at IPAA surgery was 14.4 5.23 (range 3.5-21) y. Of the 54 patients, 17 (31.5%) developed pouchitis within 5 y after IPAA. The median duration from restoration of gastrointestinal continuity to the occurrence of pouchitis was 576 999 d. Both anal resting pressure and squeezing pressure tended to be lower postoperatively than preoperatively; however, these changes were not statistically significant. Compared with open IPAA surgery, laparoscopic IPAA surgery took a significantly longer operation time (271.6 63.6 min versus 406 97.0, P ¼ 0.0002) and had lesser operative blood loss (322 407 mL versus 141 146 mL, P ¼ 0.06).
Predictive factors of pouchitis Table 2 showed the results of univariate analysis for predictive factors of the development of overall pouchitis. Univariate analysis demonstrated that total dose of steroids (P ¼ 0.0056), postoperative soiling symptoms (P ¼ 0.037), and neutrophil percentage just before colectomy (P ¼ 0.032) were the significant predictive factors for overall pouchitis. Of these three potential predictive factors for pouchitis development, total dose of steroids and neutrophil percentage were included in the receiver operating characteristic analysis for the occurrence of pouchitis to set the best cutoff values. The cutoff value for the total steroid dose was >10,000 mg before IPAA surgery, and that for neutrophil percentage was >65%. Multivariate analysis was then performed using the three categorized variables (total dose of steroids [10,000 mg or >10,000 mg], postoperative soiling [ or þ], neutrophil percentage [65% or >65%]). Multivariate analysis revealed that the factors independently associated with the development of pouchitis after IPAA were total dose of steroids (P ¼ 0.0002) and neutrophil percentage (P ¼ 0.0078, Table 3). In particular, the highest odds ratio for total steroid dose was 18.5, revealing that reducing the total dose of steroids before IPAA could have a potential protective effect in the development of pouchitis.
33/21
Age at onset of ulcerative colitis, y (median IQR)
PUCAI score at IPAA surgery (median IQR)
Results
All patients (n ¼ 54)
17.2 5.34 33.79 16.8 17/37 576 999 6350 10,512
Immunomodulator Yes/No
40/14
AntieTNF-a antibody therapy Yes/No
10/44
Preoperative anal resting pressure (median IQR)
57.5 38.7
Preoperative anal squeezing pressure (median IQR)
130 92.6
Intraoperative Type of operation Two-stage
36
Three-stage
18
Laparoscopic IPAA surgery Yes/No
11/43
Operation time at IPAA, minute (median IQR)
285 116
Operative blood loss during IPAA, mL (median IQR)
196 256
Blood transfusion Yes/No
8/46
Postoperative Surgical site infection, n (%) Postoperative anal resting pressure (median IQR) Postoperative anal squeezing pressure (median IQR)
13 (24.1%) 30.8 30.2 89 82.5
BMI ¼ body mass index; IQR ¼ interquartile range; PUCAI ¼ pediatric ulcerative colitis activity index; TNF ¼ tumor necrosis factor.
Cumulative incidence of pouchitis development Figure showed the result of the KaplaneMeier analysis divided by the relationship between the cumulative incidence of pouchitis development and the number of predictive factors (total dose of steroids >10,000 mg and neutrophil percentage >65%). The incidence of pouchitis in patients with two predictive factors (n ¼ 13) was significantly greater than that in patients with one (n ¼ 23, P ¼ 0.021) or no predictive factors (n ¼ 18, P < 0.001). The incidence of pouchitis was also
75
koike et al predictors for pediatric pouchitis
Table 2 e Univariate analysis of the potential predictors of pouchitis. Variables
Pouchitis () (n ¼ 37)
Pouchitis (þ) (n ¼ 17)
21/16
12/5
0.33
6/31
3/14
0.89
27/10
8/9
0.064
25/12
8/9
0.15
3/34
3/14
0.3
P value
General Sex Male/Female Age at onset of ulcerative colitis (y) 6/>6 Disease duration (y) 5/>5 Age at operation (y) 15/>15 Extent of colitis Left side/Total Extraintestinal manifestations Yes/No Body mass index
2/35
1/16
18.4 3.92
17.6 3.21
0.94 0.53
PUCAI score
34.59 2.80
32.05 4.09
Total dose of steroids
6794 7421
12,884 6084
25/12
15/2
0.11
6/31
4/13
0.52
0.62 0.0056
Immunomodulator Yes/No AntieTNF-a antibody therapy Yes/No Preoperative anal resting pressure
63.7 33.2
57.1 24.8
0.78
Preoperative anal squeezing pressure
147 78.9
129 54.1
0.88
Number of operation stages Two-staged/Three-staged
22/15
14/3
0.087
Type of operation Open/Laparoscopic
31/6
12/5
0.26
Operation time (min)
314 125
290 71.1
0.93
Operative blood loss (mL)
333 435
184 155
0.18
Blood transfusion Yes/No
7/30
1/16
0.21
8/29
5/12
0.53
8/9
0.037
Surgical site infection Yes/No Soiling Yes/No
7/29
Postoperative anal resting pressure
38.8 20.8
38.7 17.4
0.82
Postoperative anal squeezing pressure
100 73.4
126 77.2
0.25
WBC Count (/mm3)
9709 787
10,272 828
Neutrophil %
65.7 13.6
73.4 8.7
0.032
Hemoglobin
10.7 2.58
11.4 2.43
0.26
CRP (mg/dL)
1.27 0.29
1.54 0.84
0.56
Albumin (g/dL)
3.62 0.11
3.97 0.15
0.058
Cholinesterase (IU)
0.69 0.05
0.87 0.07
0.068
Laboratory data just before colectomy 0.25
WBC ¼ white blood cell; CRP ¼ C-reactive protein; PUCAI ¼ pediatric ulcerative colitis activity index; TNF ¼ tumor necrosis factor. The bold word meant that P value was under 0.05 (P < 0.05).
significantly greater in patients with one predictive factor compared with those with no predictive factors (P ¼ 0.043). Moreover, there was no occurrence of pouchitis in the group of patients with a score of 0 (neither of the two predictive factors).
Discussion The present study is the first study to evaluate the predictive factors for the development of pouchitis in pediatric UC that
76
j o u r n a l o f s u r g i c a l r e s e a r c h j u n e 2 0 1 9 ( 2 3 8 ) 7 2 e7 8
Table 3 e Multivariate analysis of the potential predictors of pouchitis. Variables
Odds ratio
95% CI
P value
Total dose of steroids (10,000 or >10,000)
18.5
3.75-13.0
0.0002
Postoperative soiling ( or þ) Neutrophil % (65% or >65%)
3.21 12.4
0.52-2.38
0.21
1.84-15.0
0.0078
CI ¼ confidence intervals. The bold word meant that P value was under 0.05 (P < 0.05).
has analyzed intraoperative and postoperative clinical features as well as preoperative features. The main findings of our study were that multivariate analysis identified total dose of steroids and preoperative neutrophil percentage before IPAA as independent risk factors for the subsequent development of pouchitis after IPAA. We focused on the analysis of the risk factors for the cumulative pouchitis incidence, without categorization between cumulative and chronic pouchitis incidences, while several previous studies focused on the risk factor analysis for both pouchitis types.10,13,15,18,24,25 We focused on the cumulative pouchitis incidence because identification of the risk factors for the cumulative pouchitis incidence is important in preventing or reducing the development of pouchitis, and also because the cumulative pouchitis incidence always includes the chronic pouchitis occurrence. Hence, the present results may provide useful information for the prevention of both acute and chronic pouchitis after IPAA in pediatric patients with UC. In the present study, a cumulative overdose of steroids (>10,000 mg) was an independent risk factor for pouchitis in patients with pediatric-onset UC. Preoperative steroid use has been also reported as a risk factor for the development of pouchitis.10,11,15 Fleshner et al.15 reported that the steroid administration before colectomy was associated with the development of acute pouchitis. They also demonstrated that although aggressive UC condition before the operation may be
Fig e The relationship between the cumulative incidence of pouchitis over time and the number of predictive factors present in each case. Patients with two predictive factors (score: 2) had a significantly greater incidence of pouchitis than patients with one (score: 1) or no predictive factors (score: 0). P < 0.001 for score 2 versus score 0; P [ 0.021 for score 2 versusu score 1.
a risk for pouchitis postoperatively, this trend was not seen in patients with other immunosuppressive drugs before IPAA.15 The present study also revealed that the use of immunomodulator was not a risk factor for pouchitis development. Considering these results together, when clinicians treat pediatric UC patients, switching the steroid to other immunosuppressive agents may be a better option if possible. Kalkan et al.11 also reported that a more severe preoperative clinical course and steroid dependency may be a preoperative predictors for the development of pouchitis. They suggested that aggressive disease condition during the preoperative period may be a risk factor for the development of pouchitis.11 In the present study, the total dose of steroids was a significant risk factor for pouchitis, whereas the PUCAI was not a risk factor. To check the relationship between the PUCAI and the total dose of steroids, we conducted the additional analysis between PUCAI and total steroid dose. Patients with >10,000 mg steroid were the mean 22.25 point of PUCAI, on the other hand, patient with 10,000 mg were the mean 31.12 point of PUCAI. These data indicated that patients with >10,000 mg steroid were not always in the condition of aggressive disease phenotypes. In our facility, the PUCAI score was relatively low at the time of colectomy or IPAA because we usually select the three-staged operation for pediatric patients with severe UC to reduce the occurrence of postoperative complications and also because we sometimes select the best operation timing of IPAA when preoperative inflammatory condition is lower than the admission point. In the 54 patients studied, four patients had the history of steroid pulse therapy preoperatively. Two of the four patients had developed the pouchitis (50% pouchitis rate). Unfortunately, however, we could not reveal why high amount of steroid dose was the risk factor for development of pouchitis in this study; these data also supports the relationship between the preoperative high amount of steroid dose and pouchitis development. Regarding the total dose of steroids, our patients had relatively high cumulative doses of steroids before IPAA (Table 1). In Japan, patients with intractable UC are generally treated conservatively, even when minor steroid side effects are present.26 This trend might be stronger in pediatric patients with UC compared with adults with UC, as both the physicians and the patients’ parents tend to avoid surgical treatment due to considerations of the patient’s future life. As the present results and previous reports show that steroid use is a risk factor for pouchitis, pediatric patients with UC who are being effectively treated by primary steroid administration but then experience UC relapse and need to use steroids continuously or repeatedly should be treated by IPAA surgery before their total cumulative dose of steroids becomes too high, as this may reduce the potential risk of pouchitis. The present study is the first to identify a neutrophil percentage of >65% before IPAA surgery as one of the potential risk factors for pouchitis. Yoshiyama et al.27 reported that steroid-overdosed UC patients may have a functional deficit in neutrophils (e.g., high neutrophil necrosis rate, increased release of proinflammatory cytokines, and increased release of proteolytic enzymes). In their study, UC patients were divided into two groups according to their total preoperative dosage of prednisolone (>10,000 mg, 10,000 mg). These data support our study, moreover, would be one of the possible
koike et al predictors for pediatric pouchitis
reason why high percentage of neutrophil is one of the risk factor for the development of pouchitis. In the present univariate analysis, postoperative presence of soiling symptoms (1-7 times/wk) was a significant risk factor for pouchitis, although it was not an independent risk factor for pouchitis in the multivariate analysis. The association between postoperative soiling symptoms and pouchitis development has not been previously reported, as no previous report has included the postoperative clinical features (such as soiling, and postoperative anal resting, and squeezing pressures) in the analysis of the risk factors for pouchitis. The reason for the relationship between postoperative soiling and the development of pouchitis is unclear. This symptom of soiling might affect the microbiome flora in the pouch, and further prospective analysis such as detailed classification of the microbiome in the pouch might reveal the mechanism between soiling symptoms and pouchitis development. The limitations of the present study relate to its retrospective nature and the small sample size; however, the present study included the largest sample size compared with previous studies on pediatric UC.24,25 Diagnosing pouchitis using the mPDAI may also cause diagnostic bias. Moreover, the present study included the perioperative and postoperative clinical features in the risk analysis of pouchitis, whereas the previously reported studies have not included these clinical factors; hence, it might be difficult to compare our results with previous reports that analyzed the predictive factors for pouchitis development after IPAA. Finally, the present study was unable to analyze the fecal microbiome characteristics because of its retrospective nature; a prospective analysis may help determine whether these are risk factors for pouchitis development.
Conclusion Patients with pediatric-onset UC who receive a greater cumulative dose of steroids before IPAA and those who have a greater percentage of neutrophils just before IPAA surgery may have a relatively high risk for the development of pouchitis. Although the association between these two predictive factors and a greater incidence of pouchitis remains unclear, further studies may provide novel information on the etiology of pouchitis. Using the predictive factors for pouchitis may enable us to determine which pediatric patients with UC who undergo IPAA are at high risk of developing pouchitis, give patients detailed information regarding postoperative complications (especially pouchitis), and provide an enhanced prophylaxis or treatment plan in patients with the greatest pouchitis risk.
Acknowledgment The authors thank Kelly Zammit, BVSc, from Edanz Group (www.edanzediting.com/ac), for editing a draft of this article. Authors’ contributions: Conception or design of the work was contributed by Y.K. and K.U. Data collection was carried out by Y.K., K.M., M.I., and Y.O. Data analysis was performed
77
by T.A. and M.K. Interpretation of data for the work was done by Y.T. and M.K. Manuscript was written by Y.K.
Disclosure All authors declare no conflicts of interest for this article.
references
1. Shen B, Fazio VW, Remzi FH, et al. Comprehensive evaluation of inflammatory and noninflammatory sequelae of ileal pouch-anal anastomoses. Am J Gastroenterol. 2005;100:93e101. 2. Coffey JC, Winter DC, Neary P, et al. Quality of life after ileal pouch-anal anastomosis: an evaluation of diet and other factors using the Cleveland global quality of life instrument. Dis Colon Rectum. 2002;45:30e38. 3. Shen B. Acute and chronic pouchitis–pathogenesis, diagnosis and treatment. Nat Rev Gastroenterol Hepatol. 2012;9:323e333. 4. Ferrante M, Declerck S, Coopmans T, et al. Development of pouchitis following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis: a role for serological markers and microbial pattern recognition receptor genes. J Crohns Colitis. 2008;2:142e151. 5. Fazio VW, Ziv Y, Church JM, et al. Ileal pouch-anal anastomoses complications and function in 1005 patients. Ann Surg. 1995;222:120e127. 6. Wewer V, Hesselfeldt P, Qvist N, et al. J-pouch ileoanal anastomosis in children and adolescents with ulcerative colitis: functional outcome, satisfaction and impact on social life. J Pediatr Gastroenterol Nutr. 2005;40:189e193. 7. Chew SS, Kerdic RI, Yang JL, et al. Functional outcome and quality of life after ileal pouch-anal anastomosis in children and adults. ANZ J Surg. 2003;73:983e987. 8. Alexander F, Sarigol S, DiFiore J, et al. Fate of the pouch in 151 pediatric patients after ileal pouch anal anastomosis. J Pediatr Surg. 2003;38:78e82. 9. Sarigol S, Wyllie R, Gramlich T, et al. Incidence of dysplasia in pelvic pouches in pediatric patients after ileal pouch-anal anastomosis for ulcerative colitis. J Pediatr Gastroenterol Nutr. 1999;28:429e434. 10. Okita Y, Araki T, Tanaka K, et al. Predictive factors for development of chronic pouchitis after ileal pouch-anal anastomosis in ulcerative colitis. Digestion. 2013;88:101e109. 11. Kalkan IH, Dagli U, Onder FO, et al. Evaluation of preoperative predictors of development of pouchitis after ileal-pouchanastomosis in ulcerative colitis. Clin Res Hepatol Gastroenterol. 2012;36:622e627. 12. Pardi DS, D’Haens G, Shen B, et al. Clinical guidelines for the management of pouchitis. Inflamm Bowel Dis. 2009;15:1424e1431. 13. Hoda KM, Collins JF, Knigge KL, et al. Predictors of pouchitis after ileal pouch-anal anastomosis: a retrospective review. Dis Colon Rectum. 2008;51:554e560. 14. Fleshner P, Ippoliti A, Dubinsky M, et al. Both preoperative perinuclear antineutrophil cytoplasmic antibody and antiCBir1 expression in ulcerative colitis patients influence pouchitis development after ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol. 2008;6:561e568. 15. Fleshner P, Ippoliti A, Dubinsky M, et al. A prospective multivariate analysis of clinical factors associated with pouchitis after ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol. 2007;5:952e958. quiz 887. 16. Meier CB, Hegazi RA, Aisenberg J, et al. Innate immune receptor genetic polymorphisms in pouchitis: is CARD15 a susceptibility factor? Inflamm Bowel Dis. 2005;11:965e971.
78
j o u r n a l o f s u r g i c a l r e s e a r c h j u n e 2 0 1 9 ( 2 3 8 ) 7 2 e7 8
17. Achkar JP, Al-Haddad M, Lashner B, et al. Differentiating risk factors for acute and chronic pouchitis. Clin Gastroenterol Hepatol. 2005;3:60e66. 18. Hata K, Watanabe T, Shinozaki M, et al. Patients with extraintestinal manifestations have a higher risk of developing pouchitis in ulcerative colitis: multivariate analysis. Scand J Gastroenterol. 2003;38:1055e1058. 19. Fleshner PR, Vasiliauskas EA, Kam LY, et al. High level perinuclear antineutrophil cytoplasmic antibody (pANCA) in ulcerative colitis patients before colectomy predicts the development of chronic pouchitis after ileal pouch-anal anastomosis. Gut. 2001;49:671e677. 20. Carter MJ, Di Giovine FS, Cox A, et al. The interleukin 1 receptor antagonist gene allele 2 as a predictor of pouchitis following colectomy and IPAA in ulcerative colitis. Gastroenterology. 2001;121:805e811. 21. Uchida K, Araki T, Kusunoki M. History of and current issues affecting surgery for pediatric ulcerative colitis. Surg Today. 2013;43:1219e1231.
22. Shen B, Achkar JP, Connor JT, et al. Modified pouchitis disease activity index: a simplified approach to the diagnosis of pouchitis. Dis Colon Rectum. 2003;46:748e753. 23. Shen B. Pouchitis: what every gastroenterologist needs to know. Clin Gastroenterol Hepatol. 2013;11:1538e1549. 24. Rinawi F, Assa A, Eliakim R, et al. Predictors of pouchitis after ileal pouch-anal anastomosis in pediatric-onset ulcerative colitis. Eur J Gastroenterol Hepatol. 2017;29:1079e1085. 25. Dharmaraj R, Dasgupta M, Simpson P, et al. Predictors of pouchitis after ileal pouch-anal anastomosis in children. J Pediatr Gastroenterol Nutr. 2016;63:e58ee62. 26. Shinozaki M, Suzuki K, Sawada T, et al. Steroid complications and surgery in intractable ulcerative colitis. J Gastroenterol. 1998;33:196e200. 27. Yoshiyama S, Miki C, Okita Y, et al. Neutrophil-related immunoinflammatory disturbance in steroid-overdosed ulcerative colitis patients. J Gastroenterol. 2008;43: 789e797.