Bowel movement alterations predict the severity of diverticular disease and the risk of acute diverticulitis:  a prospective, international study

Antonio Tursi; Daniele Piovani; Giovanni Brandimarte; Francesco Di Mario; Walter Elisei; Marcello Picchio; Gisella Figlioli; Gabrio Bassotti; Leonardo Allegretta; Maria Laura Annunziata; Mauro Bafutto; Maria Antonia Bianco; Raffaele Colucci; Rita Conigliaro; Dan L. Dumitrascu; Ricardo Escalante; Luciano Ferrini; Giacomo Forti; Marilisa Franceschi; Maria Giovanna Graziani; Frank Lammert; Giovanni Latella; Daniele Lisi; Giovanni Maconi; Debora Compare; Gerardo Nardone; Lucia Camara de Castro Oliveira; Chaves Oliveira Enio; Savvas Papagrigoriadis; Anna Pietrzak; Stefano Pontone; Ieva Stundiene; Tomas Poškus; Giuseppe Pranzo; Matthias Christian Reichert; Stefano Rodino; Jaroslaw Regula; Giuseppe Scaccianoce; Franco Scaldaferri; Roberto Vassallo; Costantino Zampaletta; Angelo Zullo; Erasmo Spaziani; Stefanos Bonovas; Alfredo Papa; Silvio Danese; DICA International Group

doi:10.5217/ir.2024.00046

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Original Article Bowel movement alterations predict the severity of diverticular disease and the risk of acute diverticulitis: a prospective, international study: Antonio Tursi^1,2,, Daniele Piovani^3,4, Giovanni Brandimarte⁵, Francesco Di Mario⁶, Walter Elisei⁷, Marcello Picchio⁸, Gisella Figlioli^3,4, Gabrio Bassotti⁹, Leonardo Allegretta¹⁰, Maria Laura Annunziata¹¹, Mauro Bafutto¹², Maria Antonia Bianco¹³, Raffaele Colucci¹⁴, Rita Conigliaro¹⁵, Dan L. Dumitrascu¹⁶, Ricardo Escalante¹⁷, Luciano Ferrini¹⁸, Giacomo Forti¹⁹, Marilisa Franceschi²⁰, Maria Giovanna Graziani²¹, Frank Lammert^22,23, Giovanni Latella²⁴, Daniele Lisi²⁵, Giovanni Maconi²⁶, Debora Compare²⁷, Gerardo Nardone²⁷, Lucia Camara de Castro Oliveira²⁸, Chaves Oliveira Enio²⁹, Savvas Papagrigoriadis³⁰, Anna Pietrzak³¹, Stefano Pontone³², Ieva Stundiene³³, Tomas Poškus³³, Giuseppe Pranzo³⁴, Matthias Christian Reichert²², Stefano Rodino³⁵, Jaroslaw Regula³¹, Giuseppe Scaccianoce³⁶, Franco Scaldaferri³⁷, Roberto Vassallo³⁸, Costantino Zampaletta³⁹, Angelo Zullo⁴⁰, Erasmo Spaziani⁴¹, Stefanos Bonovas^3,4, Alfredo Papa³⁷, Silvio Danese⁴², DICA International Group; DOI: https://doi.org/10.5217/ir.2024.00046
Published online: August 12, 2024

¹Territorial Gastroenterology Service, ASL BAT, Andria, Italy

²Department of Medical and Surgical Sciences, School of Medicine, Catholic University, Rome, Italy

³Department of Biomedical Sciences, Humanitas University, Milan, Italy

⁴IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

⁵Division of Internal Medicine and Gastroenterology, Hospital, Rome, Italy

⁶Department of Medical and Surgical Sciences, Gastroenterology Unit, University of Parma, Parma, Italy

⁷Division of Gastroenterology, Hospital, Rome, Italy

⁸Division of Surgery, Hospital, ASL RM6, Velletri, Italy

⁹Department of Medicine and Surgery, Gastroenterology and Hepatology Unit, University Hospital, University of Perugia, Perugia, Italy

¹⁰Division of Gastroenterology, Hospital, Galatina, Italy

¹¹Division of Gastroenterology, Hospital, San Donato Milanese, Italy

¹²Institute of Gastroenterology and Digestive Endoscopy, Goiânia, Brazil

¹³Division of Gastroenterology, Hospital, Torre del Greco, Italy

¹⁴Digestive Endoscopy Unit, Hospital, Spoleto, Italy

¹⁵Digestive Endoscopy Unit, Hospital, Baggiovara, Italy

¹⁶Second Medical Department, University of Medicine and Pharmacy, Cluj-Napoca, Romania

¹⁷Central University of Venezuela, Loira Medical Center, Caracas, Venezuela

¹⁸Service of Digestive Endoscopy, Home Care, Civitanova Marche, Italy

¹⁹Digestive Endoscopy Unit, Hospital, Latina, Italy

²⁰Digestive Endoscopy Unit, ULSS 7 Alto Vicentino, Santorso, Italy

²¹Division of Gastroenterology and Digestive Endoscopy, Hospital, Rome, Italy

²²Department of Medicine II, Saarland University Medical Center, Homburg, Germany

²³Health Sciences, Hannover Medical School (MHH), Hannover, Germany

²⁴Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health & Environmental Sciences, San Salvatore Hospital, University of L’Aquila, L’Aquila, Italy

²⁵Territorial Gastroenterology Service, ASL Rm B, Rome, Italy

²⁶Division of Gastroenterology, University Hospital, Milan, Italy

²⁷Department of Clinical Medicine and Surgery, Division of Gastroenterology and Hepatology, Federico II” University Hospital, Naples, Italy

²⁸Department of Anorectal Physiology, Home Care, Rio de Janeiro, Brazil

²⁹Department of Colorectal Surgery, Federal University of Goiás, Goiânia, Brazil

³⁰Department of Colorectal Surgery, King’s College Hospital, London, UK

³¹Department of Gastroenterology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education and Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland

³²First Division of General Surgery, University Hospital, University, Rome, Italy

³³Institute of Clinical Medicine, Vilnius University Hospital, Vilnius, Lithuania

³⁴Digestive Endoscopy Unit, Hospital, Martina Franca, Italy

³⁵Division of Gastroenterology, Hospital, Catanzaro, Italy

³⁶Digestive Endoscopy Unit, Hospital, Altamura, Italy

³⁷Division of Internal Medicine and Gastroenterology, IRCCS Hospital, Fondazione Policlinico Gemelli, Catholic University, Rome, Italy

³⁸Division of Gastroenterology and Digestive Endoscopy, Hospital, Palermo, Italy

³⁹Division of Gastroenterology, Hospital, Viterbo, Italy

⁴⁰Division of Gastroenterology, Hospital, Rome, Italy

⁴¹Department of Surgery, University of Rome-Polo Pontino, Terracina, Italy

⁴²Gastroenterology and Endoscopy, IRCCS Ospedale and University, Milan, Italy

Correspondence to Antonio Tursi, Territorial Gastroenterology Service, ASL BAT, Via Torino, 49, Andria 76123, Italy. Tel: +39-883-551094, Fax: +39-883-1978210, E-mail: antotursi@tiscali.it

• Received: March 22, 2024 • Revised: May 1, 2024 • Accepted: May 8, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
INTRODUCTION
METHODS
RESULTS
DISCUSSION
NOTES
Supplementary Material
REFERENCES
Appendix

Abstract

Background/Aims
Patients with diverticular disease (DD) frequently have abnormal bowel movements. However, it is unknown whether the entity of these alterations is associated with the severity of DD. We aimed to assess bowel habits and their relationship with the severity of DD according to Diverticular Inflammation and Complication Assessment (DICA) classification, Combined Overview on Diverticular Assessment (CODA) score, and fecal calprotectin (FC).
Methods
An international, multicenter, prospective cohort study was conducted in 43 centers. A 10-point visual analog scale (VAS) was used to assess the severity of constipation and diarrhea. The association of constipation and diarrhea with DICA classification, CODA score, and basal FC was tested using non-parametric tests. Survival methods for censored observations were applied to test the association of constipation and diarrhea with the incidence of acute diverticulitis over a 3-year follow-up.
Results
Of 871 patients with DD were included in the study. Of these, 208 (23.9%) and 199 (22.9%) reported a VAS score for constipation and diarrhea at least 3 at baseline, respectively. Higher constipation and diarrhea scores were associated with increasing DICA classification, CODA score and basal FC (P<0.001). Constipation and diarrhea scores were independently associated with an increased hazard of developing acute diverticulitis (hazard ratio [HR]_constipation = 1.15 per 1-VAS point increase, 95% confidence interval [CI], 1.04–1.27; P=0.004; and HR_diarrhea =1.14; 95% CI, 1.03–1.26; P=0.014, respectively).
Conclusions
In newly diagnosed patients with DD, higher endoscopic and combined scores of DD severity were associated with higher scores of constipation and diarrhea at baseline. Both constipation and diarrhea were independent prognostic factors of acute diverticulitis.
Keywords: Bowel frequency; Diverticular diseases; Diverticular Inflammation and Complication Assessment classification; Fecal calprotectin; Acute diverticulitis

INTRODUCTION

The prevalence of diverticulosis of the colon and its clinical manifestation, diverticular disease (DD), have shown significant increments in the last few years [1]. The severity of DD is currently scored according to clinical [2], radiological [3], and endoscopic classifications [4], and much is known about its management [1]. Despite this, little is currently known about the pathogenesis of diverticulosis and DD [5], in particular about the role of fecal output and its severity in the pathophysiology of the disease.

Constipation has been considered the mainstay of the disease for many years [5], but recent studies seem to exclude this association [6,7]. At the same time, diarrhea seems to be more frequent in patients with diverticulosis [8,9], and patients reporting diarrhea seem to be at higher risk of acute diverticulitis [10]. However, this association has yet to be investigated in depth in patients with DD, and no data are currently available about the relationship between the type and entity of fecal output and the severity of DD.

DICA (Diverticular Inflammation and Complication Assessment) endoscopic classification (Supplementary Table 1) and CODA (Combined Overview on Diverticular Assessment) clinical score (Supplementary Table 2) have recently shown their effectiveness in predicting the outcome of the DD [4]. Their predictive role was enhanced when associated with fecal calprotectin (FC) expression [11].

This study aimed to assess the fecal output of patients with diverticulosis and DD and investigate the association of bowel habits with the severity of the DD, measured according to the DICA endoscopic score, CODA clinical score, and FC expression.

METHODS

1. Study Design and Study Aims

This is a post-hoc analysis of a previously published, multicenter, prospective cohort study including patients with diverticulosis/DD diagnosed by endoscopy in 43 international centers in Italy, Germany, United Kingdom, Poland, Romania, Lithuania, Brazil, and Venezuela [4]. In detail, the studied population is a subgroup of 871 patients from the original cohort of 2,198 patients used to validate the DICA endoscopic classification for diverticulosis/DD and to develop the CODA clinical score for diverticulosis/DD [4], in which all patients underwent FC dosing at the baseline visit.

2. Participants

In the original prospective study, only patients at the first diagnosis of diverticulosis/DD (i.e., newly diagnosed DD patients) were enrolled. A common database to collect demographic and clinical data was built. Regarding symptoms, simplified definitions of constipation: the passage of fewer than 3 stools per week and/or having a difficult time in passing stools and diarrhea; the passage of more than 3 stools per day and/or often semiliquid or liquid stools consistency, were adopted [12]. They were based on the Bristol Stool Form Scale [13].

Inclusion criteria were age > 18 years, and first endoscopic diagnosis of diverticulosis; exclusion criteria were radiological signs (by abdominal computed tomography or by ultrasounds) of acute diverticulitis (defined as inflammation of colonic wall harboring diverticula with fat stranding, and with or without complications such as abscesses, stenosis or fistulas, namely uncomplicated or complicated diverticulitis) [1]; inflammatory bowel diseases; ischemic colitis; infectious colitis; prior colonic resection; patients with severe liver failure (Child-Pugh C); patients with severe kidney failure; pregnant women; women of childbearing potential not using a highly effective method of contraception; patients with current use or who have received any laxative agents < 2 weeks prior to the enrollment; patients with recent use or who have received mesalamine compounds < 2 weeks prior to the enrollment; patients with current use or who have received any probiotic agents 2 weeks prior to the enrollment; nonsteroidal anti-inflammatory drug use (except for acetylsalicylic acid ≤ 100 mg/day) < 1 week prior to the enrollment; patients who have received treatment with antibiotics (even those not absorbed) < 2 weeks prior to the enrollment; inability to comply with study protocol and to give informed consent to the procedure; patients with or history of cancer, of any origin, within 5 years before enrollment; history of alcohol, drug, or chemical abuse; any severe pathological condition interfering with the proper study execution. Further data about the study’s design were reported in the original study [4].

Patients were scored according to DICA classification and CODA score [4]. Since our initial study protocol did not plan centralized laboratory analysis of FC, we considered only valid FC measurements deriving from quantitative assays expressed in µg/g to homogenize and increase the comparability across centers.

Our aims were: (1) to evaluate the frequency of constipation and diarrhea in patients with diverticulosis/DD; (2) to evaluate the severity of constipation and diarrhea in those patients; (3) to estimate the association between constipation and diarrhea with the severity of diverticulosis/DD according to DICA classification, CODA score and FC expression at baseline [14]; and (4) to assess the association between constipation and diarrhea and development of acute diverticulitis over the follow-up.

3. Statistical Analysis

Descriptive statistics include medians and interquartile ranges (IQRs) for continuous variables and frequency analyses (percentages) for categorical variables. The frequency and severity of constipation and diarrhea were measured using a 10-point visual analog scale (VAS), ranging from 0: absence to 10: maximal severity. The association of constipation and diarrhea with the severity of diverticulosis/DD was assessed by comparing the 10-point VAS scores across groups defined by the DICA classification, CODA score and basal FC. The 2-sample Wilcoxon rank-sum and the Kruskal-Wallis tests were used to compare continuous variables across groups.

The association of constipation and diarrhea, measured at baseline, with the risk of developing acute diverticulitis was assessed by time-to-event (survival) methods for censored observations. Time-to-event was defined as the time (in months) from the baseline visit until the event date or censoring. Cox regression was performed by running 2 univariable models testing the effects of constipation and diarrhea separately as continuous variables. We also examined whether the associations of constipation and diarrhea with acute diverticulitis were independent by fitting a multivariable model including both constipation and diarrhea jointly while adjusting for the potential confounding effect of age and sex [9,10]. A previous study on the association between bowel movements and diverticulitis found that age categories, body mass index, physical activity, laxative use or fiber intake did not modify the association [10]. As the current study has an etiological scope, we considered this evidence and adjusted only for sex and age as a continuous variable. We retained the adjustment by age as the previous study considered age as a categorical variable, which could have yielded a lack of statistical power to detect an effect. The Kaplan-Meier estimates were employed to plot the cumulative incidence of diverticulitis in groups of patients defined by the absence (VAS = 0) or presence (VAS > 0) of any symptoms of constipation and diarrhea. Log-rank tests were performed to compare the plotted curves. Two-tailed P<0.05 was considered to indicate statistical significance. Stata software version 17 (StataCorp LLC, College Station, TX, USA) was used for analysis.

4. Ethics Approval

The study was conducted according to the 1975 World Medical Association Declaration of Helsinki and was approved by the Ethic Committees of the coordinator center (Prot.64/SCE/2015) and all participating centers. All study participants provided informed written consent before the endoscopic investigation and to participate in this study.

RESULTS

Baseline demographic and clinical characteristics are reported in Table 1. Patients were predominantly males (50.4%) with a median age of 65 years (IQR, 56–72 years). They were slightly overweight (median body mass index, 26 kg/m²; IQR, 23.2–28.9 kg/m²), and 28.2% were smokers. Most patients (56.0%) had a DD corresponding to the DICA 1 classification, 32.1% DICA 2, and 11.9% DICA 3. After considering DICA classification, age and abdominal pain score, the CODA score was computed for each patient (median CODA score, 10; IQR, 7–16). Basal FC varied widely across patients, ranging from 8 to 1,800 μg/g, with a median of 25 μg/g (IQR, 12–70 μg/g).

Sixty-five acute diverticulitis events occurred during an average follow-up of 2.8 years. The cumulative incidence of diverticulitis was 26.5 per 1,000 person-years, corresponding to an estimated 3-year risk of 7.6% (95% confidence interval [CI], 6.0%−9.6%).

The scores of constipation and diarrhea increased with increasing DICA classification (Kruskal-Wallis test, P<0.001) (Fig. 1A and B) and increasing CODA scores (Kruskal-Wallis test, P<0.001) (Fig. 1C and D). Similarly, higher scores of constipation and diarrhea were associated with higher basal FC (Wilcoxon rank-sum test, P<0.01) (Fig. 1E and F).

Cox regression analyses evaluated the effect of constipation and diarrhea on the incidence of acute diverticulitis. At the univariable analysis, we found evidence of a significant association between the scores of constipation and diarrhea and the risk of developing acute diverticulitis over the 3‐year follow‐up (hazard ratio [HR]_constipation, 1.12 per 1-VAS point increase; 95% CI, 1.02–1.23; P=0.019; HR_diarrhea, 1.11 per 1-VAS point increase; 95% CI, 1.00–1.22; P=0.047, respectively).

The results were confirmed in the multivariable model, which tested the association of both variables jointly and adjusted them by age and sex. There was a 15% increase in the hazard of acute diverticulitis per each point increase in the score of constipation (HR_constipation, 1.15; 95% CI, 1.04–1.27; P=0.004) and a 14% increase in the hazard of acute diverticulitis per each point increase in the score of diarrhea (HR_diarrhea, 1.14; 95% CI, 1.03–1.26; P=0.014) (Table 2). Both effects were independent of each other.

The estimated 3‐year cumulative probability of diverticulitis was 5.9% (95% CI, 4.1%–8.3%) in patients without symptoms of constipation (i.e., VAS_constipation = 0) and 10.0% (95% CI, 7.0%–13.7%) in patients with these specific symptoms (VAS_constipation > 0), which significantly differed across the strata (log‐rank test, P=0.03) (Fig. 2A). Similarly, the estimated 3‐year cumulative probability of diverticulitis was 6.2% (95% CI, 4.4%–8.6%) in patients with no symptoms of diarrhea (VAS_diarrhea = 0) and 9.7% (95% CI, 6.6%–13.5%) in patients with VAS_diarrhea > 0. However, this latter difference was slightly above the statistical significance threshold (log‐rank test, P=0.06) (Fig. 2B).

DISCUSSION

Although the worldwide DD prevalence is well known, and its main complication, acute diverticulitis, is now easy to recognize, it is still unclear whether bowel habits frequency may be linked to the severity of the disease and/or with the risk of acute diverticulitis. In particular, whether constipation or diarrhea is related to the risk of developing acute diverticulitis.

For many years, DD has been thought to be strictly linked to constipation. In particular, the demonstration that defecation in a sitting position, with a reduction of the anorectal angle and increase of intra-colonic pressure [15], has been considered one of the causes of the increasing prevalence of DD in the Western World. However, several studies from the United States [6-8,16] and Japan [9,17] failed to find an association between constipation and diverticulosis. On the contrary, diarrhea and loose stools were associated with DD in the United States [16] and Japan [14]. And looking at the risk of acute diverticulitis according to bowel habits frequency, it has been recently shown that diarrhea, not constipation, may be a risk factor for acute diverticulitis, especially in women [10]. However, these symptoms have only sometimes been compared with the severity of the disease nor with FC expression.

This is the first study in which the frequency of bowel habits was compared with the severity of DD using objective methods. We found that higher scores of constipation and diarrhea at baseline correlated with higher endoscopic (i.e., DICA) and composite (CODA) scores of DD severity. This means that patients undergoing colonoscopy and complaining of abnormal bowel habits are at higher risk of having a more severe disease, whether diverticulosis is detected. Why this occurs is unknown. Colonic motility, which in these patients often displays abnormal motor patterns frequently associated with pain [18], is likely to play an important role, as also shown by the abnormalities of the enteric nervous system reported in patients with DD [19]. Also, bowel habit abnormalities may be linked to intraluminal factors. There is evidence that stool consistency [20,21] and bowel movement frequency [22,23] may modify the intestinal microbiome, even though it is not known whether altered gut motility influences [22,23] the changes in the gut microbiome or is influenced by the changes in the gut microbiome [24,25]. However, the recent observations about the changes in colonic microbiome in acute diverticulitis, even according to the severity of the disease [26], may shed light on potential mechanisms that underlie the association between severity of bowel movement frequency, severity of DD and risk of acute diverticulitis.

Intestinal inflammation may also be essential in determining the risk of acute diverticulitis in those patients, as shown by the presence of low-grade inflammation in mucosa biopsy [27] and resected surgical specimens [28]. We recently reported that FC of 90 μg/g is the cutoff for the risk of acute diverticulitis [11]. In the present study, we found that higher scores of constipation and diarrhea were associated with higher basal FC, thus suggesting that higher scores of constipation and diarrhea are associated with higher inflammation, which might lead to acute diverticulitis. The detection of myenteric plexitis (namely, the infiltration of myenteric ganglions by inflammatory cells) in patients undergoing surgery for DD seems to confirm this hypothesis [28].

Whatever the underlying mechanisms, we found that constipation and diarrhea are independent risk factors for acute diverticulitis. This is an important point because, after adjusting for sex and age (factors potentially influencing the risk of acute diverticulitis occurrence) [9,10], each of these bowel habits may independently affect the outcome of the disease. This result is strengthened by the multivariate analysis showing that, after adjusting for age and sex, each point of constipation score increased the risk of acute diverticulitis by approximately 15%, and each point of diarrhea score increased this risk by about 14%. This means that not only the severity of constipation or diarrhea in patients with DD is associated with the severity of the disease, but also that the increase in the score of constipation or diarrhea increases the hazard of acute diverticulitis. This means that not only the severity of constipation or diarrhea is associated with the severity of DD, but also that the higher constipation or diarrhea score, the higher hazard of acute diverticulitis. Putting all together these data, we can draw essential recommendations for the clinical practice: patients having diverticulosis and complaining of more severe constipation or diarrhea may have worse endoscopic and inflammation scores and are at increased risk of developing diverticulitis, thus needing closer monitoring.

We are aware that this study has some limitations. For instance, we do not have information about diet; a high-fiber diet is still recommended to prevent DD complications [29]. Thus, we cannot exclude that constipation or diarrhea may be due to a lower or higher volume of fiber intake. Another area for improvement is the need for more information on ongoing treatments for bowel habit alterations. Unfortunately, these data were unavailable during patients’ enrollment, and this post-hoc analysis does not permit overcoming this limitation. Lastly, the study was conducted on a subset of patients with valid FC measurements. We recognize this may introduce a selection of participants and, therefore, partially limit the generalizability of the findings.

In conclusion, this prospective cohort study showed that higher diarrhea and constipation scores at baseline predicted higher endoscopic (i.e., DICA) and composite (i.e., CODA) scores of DD severity and higher FC levels. Moreover, both constipation and diarrhea were independent prognostic factors of acute diverticulitis. Additional studies are needed to elucidate this association’s potential mechanisms, providing new targets for managing DD and preventing acute diverticulitis.

NOTES

Funding Source

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

Tursi A served as speaker and/or consultant for AbbVie, Galápagos, Janssen, Nalkein, and Omega Pharma. Maconi G served as speaker and/or advisory board fees for AlfaSigma, Arena, Janssen, Gilead, and Roche. Nardone G received funding for target projects from Apharm and Sofar. Pietrzak A served as a lecturer for AlfaSigma and Polpharma. Regula J served as a lecturer for AlfaSigma, Takeda, Ipsen, and Servier. Scaldaferri F served as a lecturer for AbbVie, Celltrion, Ferring, Janssen, Lilly, Pfizer, Sanofi, and Takeda. Papa A served as a speaker for Janssen. Danese S served as speaker, consultant, and/or advisory board member for AbbVie, Allergan, Alfa Wassermann, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Johnson & Johnson, Merck, MSD, Mundipharma, Pfizer Inc., Sandoz, Takeda, Tigenix, UCB Pharma, Vifor. The remaining authors declare no competing interests.

Data Availability Statement

All data and related metadata underlying the findings reported in the manuscript are deposited in an appropriate public repository, unless already provided as part of the article.

Author Contributions

Conceptualization: Tursi A, Brandimarte G, Di Mario F. Data curation: Tursi A, Elisei W, Picchio M, Piovani D, Figlioli G, Bonovas S. Investigation: Tursi A, Piovani D, Brandimarte G, Di Mario F, Elisei W, Picchio M, Figlioli G, Bassotti G, Allegretta L, Annunziata ML, Astegiano M*, Bachetti F*, Bafutto M, Bianco MA, Colucci R, Conigliaro R, Dumitrascu DL, Escalante R, Ferrini L, Fiorella S*, Forti G, Franceschi M, Graziani MG, Lammert F, Latella G, Maconi G, Nardone G, Camara de Castro Oliveira L, Chaves Oliveira E, Papagrigoriadis S, Pietrzak A, Pontone S, Portincasa P*, Stundiene I, Pranzo G, Reichert MC, Rizzo GL*, Rodino S*, Regula J, Scaccianoce G, Scaldaferri F, Schiffino L*, Vassallo R, Zampaletta C, Zullo A, Spaziani E, Papa A, Danese S, Baldassarre G*, Baldi F†, Borsotti E*, Cassieri C*, Cazzato A*, Chiri S*, Ciccone A*, Compare D, Damiani A*, De Colibus P*, Faggiani R*, Finocchiaro F*, Foschia F*, Furfaro F*, Gallina S*, Giorgetti G*, Grad S*, Grande G*, Grandolfo A*, Lai MA*, Lecca PG*, Lisi D, Lopetuso LR*, Penna A*, Pigo F*, Rizzatti G*, Scanni S*, Poškus T, Tesoriere A*, Urgesi R*, Usai P*. Methodology: Piovani D, Figlioli G, Bonovas S. Project administration: Tursi A, Brandimarte G, Di Mario F. Resources: Tursi A, Piovani D, Brandimarte G, Di Mario F, Elisei W, Picchio M, Figlioli G, Bassotti G, Allegretta L, Annunziata ML, Astegiano M*, Bachetti F*, Bafutto M, Bianco MA, Colucci R, Conigliaro R, Dumitrascu DL, Escalante R, Ferrini L, Fiorella S*, Forti G, Franceschi M, Graziani MG, Lammert F, Latella G, Maconi G, Nardone G, Camara de Castro Oliveira L, Chaves Oliveira E, Papagrigoriadis S, Pietrzak A, Pontone S, Portincasa P*, Stundiene I, Pranzo G, Reichert MC, RIZZO GL*, Rodino S*, Regula J, Scaccianoce G, Scaldaferri F, Schiffino L*, Vassallo R, Zampaletta C, Zullo A, Spaziani E, Papa A, Danese S, Baldassarre G*, Baldi F†, Borsotti E*, Cassieri C*, Cazzato A*, Chiri S*, Ciccone A*, Compare D, Damiani A*, De Colibus P*, Faggiani R*, Finocchiaro F*, Foschia F*, Furfaro F*, Gallina S*, Giorgetti G*, Grad S*, Grande G*, Grandolfo A*, Lai MA*, Lecca PG*, Lisi D, Lopetuso LR*, Penna A*, Pigo F*, Rizzatti G*, Scanni S*, Poškus T, Tesoriere A*, Urgesi R*, Usai P*. Supervision: Tursi A. Validation: Tursi A, Elisei W, Picchio M, Piovani D, Figlioli G, Bonovas S. Visualization: Tursi A, Elisei W, Picchio M, Piovani D, Figlioli G, Bonovas S. Writing - original draft: Tursi A, Piovani D, Figlioli G. Writing - review & editing: Tursi A, Piovani D, Figlioli G, Bonovas S, Bassotti G, Lammert F, Latella G, Maconi G, Nardone G, Tomas Poskus, Regula J, Scaldaferri F, Papa A, Danese S. Approval of final manuscript: All authors.

^*DICA International Group (Appendix 1); ^†Fabio Baldi, MD deceased

Supplementary Material

Supplementary materials are available at the Intestinal Research website (https://www.irjournal.org).

Supplementary Table 1.

Items Assessed in Constructing DICA Endoscopic Classification

ir-2024-00046-Supplementary-Table-1.pdf

Supplementary Table 2.

CODA Score: Scoring System

ir-2024-00046-Supplementary-Table-2.pdf

Fig. 1.

Box plots showing the distribution of symptoms scores for constipation and diarrhea (10-point VAS) across groups of patients def ined by DICA endoscopic classification levels (A, B), CODA score (C, D), and basal FC (E, F). Constipation and diarrhea 10-point VASs were tested as continuous variables across the DICA classification levels and CODA scores by applying the Kruskal-Wallis test (A-D; P<0.001) and across the 2 categories of FC by using the Wilcoxon rank-sum test (E, F; P<0.01). VAS, visual analog scale; DICA, Diverticular Inflammation and Complication Assessment; CODA, Combined Overview on Diverticular Assessment; FC, fecal calprotectin.

Fig. 2.

Kaplan-Meier curves of the cumulative incidence of acute diverticulitis. (A) Comparison between patients without symptoms of constipation (10-point VAS=0) and patients reporting any symptom of constipation (10-point VAS ≥1). (B) Comparison between patients without symptoms of diarrhea (10-point VAS=0) and patients reporting any diarrhea (10-point VAS ≥1). Two-sided P-values from log-rank tests are reported. VAS, visual analog scale.

Table 1.

Baseline Demographic and Clinical Characteristics of the Study Population

Characteristic	Value (n = 871)
Age (yr)	65 (56–72)
≥ 65	451 (51.8)
Male sex	439 (50.4)
Body mass index (kg/m²)	26.0 (23.2–28.9)
≥ 30	166 (19.1)
Smoking
Smokers	246 (28.2)
Non-smokers	513 (58.9)
Ex-smokers	112 (12.8)
Appendectomy	224 (25.7)
Presence of co-morbidities
Charlson’s score	3 (2–4)
Charlson’s score > 3	220 (25.2)
Presence of any symptom	682 (78.3)
Cumulative symptom score^a	8 (2–13)
>7	441 (50.6)
Abdominal pain	2 (0–5)
>2	404 (46.4)
Bloating	2 (0–4)
>2	371 (42.6)
Constipation
Absent (0)	539 (62.0)
Mild (1 or 2)	123 (14.1)
Moderate to severe (> 2)	208 (23.9)
Diarrhea
Absent (0)	561 (64.4)
Mild (1 or 2)	111 (12.7)
Moderate to severe (> 2)	199 (22.9)
DICA classification
1	488 (56.0)
2	279 (32.1)
3	104 (11.9)
CODA score	10 (7–16)
Fecal calprotectin (μg/g)	25 (12–70)
> 90	151 (17.3)

Values are presented as median (interquartile range) or number (%).

^a The cumulative symptom score ranges from 0 to 40 points. It is obtained by adding the points regarding abdominal pain, meteorism, constipation, and diarrhea as measured on a 10-point visual analog scale.

DICA, Diverticular Inflammation and Complication Assessment; CODA, Combined Overview on Diverticular Assessment.

Table 2.

Effect of Constipation and Diarrhea on the Risk of Acute Diverticulitis: Time-to-Event Analysis

Baseline parameter	Multivariable Cox PH model
Baseline parameter	HR (95% CI)	P-value
Constipation (per 1-VAS point increase)	1.15 (1.04–1.27)	0.004
Diarrhea (per 1-VAS point increase)	1.14 (1.03–1.26)	0.014
Sex (males vs. females)	1.51 (0.92–2.49)	0.104
Age (per 1-yr increase)	0.97 (0.95–0.99)	0.016

PH, proportional-hazard; HR, hazard ratio; CI, confidence interval; VAS, visual analog scale.

REFERENCES

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4. Tursi A, Brandimarte G, Di Mario F, et al. Prognostic performance of the ‘DICA’ endoscopic classification and the ‘CODA’ score in predicting clinical outcomes of diverticular disease: an international, multicentre, prospective cohort study. Gut 2022;71:1350–1358.Article PubMed
5. Kupcinskas J, Strate LL, Bassotti G, et al. Pathogenesis of diverticulosis and diverticular disease. J Gastrointestin Liver Dis 2019;28(suppl 4): 7–10.Article
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10. Jovani M, Ma W, Staller K, et al. Frequency of bowel movements and risk of diverticulitis. Clin Gastroenterol Hepatol 2022;20:325–333.Article PubMed
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Appendix

Appendix 1.

DICA International Group (to Be Indexed to the Paper and in PubMed)

Name	Surname	Affiliation(s)
Marco	Astegiano	Division of Gastroenterology, “Molinette” University Hospital, Torino, Italy
Francesco	Bachetti	Department of Medicine and Surgery, Gastroenterology and Hepatology Unit, “Santa Maria Della Misericordia” University Hospital, University of Perugia, Perugia, Italy
Gianluca	Baldassarre	Digestive Endoscopy Unit, ULSS7 Alto Vicentino, Santorso (VI), Italy
Fabio	Baldi^†	Digestive Endoscopy Unit, Civil Hospital, Tarquinia (VT), Italy
Edoardo	Borsotti	Division of Gastroenterology, “San Donato” Hospital, San Donato Milanese (MI), Italy
Claudio	Cassieri	Division of Internal Medicine and Gastroenterology, “Cristo Re” Hospital, Rome, Italy
Alessia	Cazzato	Division of Gastroenterology, “Santa Caterina Novella” Hospital, Galatina (LE), Italy
Stefania	Chiri	Division of Gastroenterology, “Santa Caterina Novella” Hospital, Galatina (LE), Italy
Antonio	Ciccone	Division of Gastroenterology, Hepatology and Nutrition, San Salvatore Hospital, Department of Life, Health & Environmental Sciences, University of L'Aquila, L’Aquila, Italy
Alberto	Damiani	Service of Digestive Endoscopy, “Villa dei Pini” Home Care, Civitanova Marche (MC), Italy
Patrizia	De Colibus	Division of Gastroenterology, “T. Maresca” Hospital, Torre del Greco (NA), Italy
Roberto	Faggiani	Division of Gastroenterology, “S. Camillo” Hospital, Rome, Italy
Fabio	Finocchiaro	Division of Gastroenterology, “Molinette” University Hospital, Torino, Italy
Serafina	Fiorella	Division of Gastroenterology, “San Pio da Pietrelcina” Hospital, Vasto (CH), Italy
Francesca	Foschia	Territorial Gastroenterology Service, ASL Roma 2, Rome, Italy
Federica	Furfaro	Gastroenterology and Endoscopy, IRCCS Ospedale "San Raffaele" and University "Vita-Salute San Raffaele", Milan, Italy
Sara	Gallina	Division of Gastroenterology, “Belcolle” Hospital, Viterbo, Italy
Gian Marco	Giorgetti	Digestive Endoscopy and Nutritional Unit, “S. Eugenio” Hospital, Rome, Italy
Simona	Grad	2nd Medical Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
Giuseppe	Grande	Digestive Endoscopy Unit, “Sant’Agostino Estense” Hospital, Baggiovara (MO), Italy
Antonio	Grandolfo	Division of Gastroenterology, “S. Paolo” Hospital, Bari - Italy
Maria Antonia	Lai	Division of Gastroenterology, “Monserrato” University Hospital, University of Cagliari, Cagliari, Italy
Piera Giuseppina	Lecca	Division of Internal Medicine and Gastroenterology, “Cristo Re” Hospital, Rome, Italy
Loris Riccardo	Lopetuso	Division of Internal Medicine and Gastroenterology, IRCCS “A. Gemelli” Hospital, Fondazione Policlinico Gemelli, Catholic University, Rome, Italy; Department of Medicine and Ageing Sciences, ”G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy; Center for Advanced Studies and Technology (CAST), “G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy
Antonio	Penna	Territorial Gastroenterology Service, ASL Bari, Bari, Italy
Flavia	Pigo	Digestive Endoscopy Unit, “Sant’Agostino Estense” Hospital, Baggiovara (MO), Italy
Piero	Portincasa	Internal Medicine Unit, “A. Murri” Medical Clinic, Policlinico University Hospital, Bari, Italy
Giannenrico	Rizzatti	Division of Internal Medicine and Gastroenterology, IRCCS “A. Gemelli” Hospital, Fondazione Policlinico Gemelli, Catholic University, Rome, Italy
Giovanni Luca	Rizzo	Division of Gastroenterology, “Perrino” Hospital, Brindisi, Italy
Stefano	Rodino	Division of Gastroenterology, “Pugliese-Ciaccio” Hospital, Catanzaro, Italy
Stefania	Scanni	Territorial Gastroenterology Service, ASL Roma 2, Rome, Italy
Luigi	Schiffino	Division of Gastroenterology and Surgical Endoscopy, “Grassi” Hospital, Ostia, Rome, Italy
Erasmo	Spaziani	Department of Surgery, “Sapienza” University of Rome-Polo Pontino, Terracina (LT), Italy
Antonino	Tesoriere	Digestive Endoscopy Unit, Civil Hospital, Tarquinia (VT), Italy
Riccardo	Urgesi	Division of Gastroenterology and Digestive Endoscopy “S. Giovanni-Addolorata” Hospital, Rome, Italy
Paolo	Usai	Division of Gastroenterology, “Monserrato” University Hospital, University of Cagliari, Cagliari, Italy

^† The co-author Fabio Baldi, MD deceased.

Figure & Data

REFERENCES

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Bowel movement alterations predict the severity of diverticular disease and the risk of acute diverticulitis: a prospective, international study

DOI: https://doi.org/10.5217/ir.2024.00046

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Figure

Bowel movement alterations predict the severity of diverticular disease and the risk of acute diverticulitis: a prospective, international study

Fig. 1. Box plots showing the distribution of symptoms scores for constipation and diarrhea (10-point VAS) across groups of patients def ined by DICA endoscopic classification levels (A, B), CODA score (C, D), and basal FC (E, F). Constipation and diarrhea 10-point VASs were tested as continuous variables across the DICA classification levels and CODA scores by applying the Kruskal-Wallis test (A-D; P<0.001) and across the 2 categories of FC by using the Wilcoxon rank-sum test (E, F; P<0.01). VAS, visual analog scale; DICA, Diverticular Inflammation and Complication Assessment; CODA, Combined Overview on Diverticular Assessment; FC, fecal calprotectin.

Fig. 2. Kaplan-Meier curves of the cumulative incidence of acute diverticulitis. (A) Comparison between patients without symptoms of constipation (10-point VAS=0) and patients reporting any symptom of constipation (10-point VAS ≥1). (B) Comparison between patients without symptoms of diarrhea (10-point VAS=0) and patients reporting any diarrhea (10-point VAS ≥1). Two-sided P-values from log-rank tests are reported. VAS, visual analog scale.

Fig. 1.

Fig. 2.

Bowel movement alterations predict the severity of diverticular disease and the risk of acute diverticulitis: a prospective, international study

Characteristic	Value (n = 871)
Age (yr)	65 (56–72)
≥ 65	451 (51.8)
Male sex	439 (50.4)
Body mass index (kg/m²)	26.0 (23.2–28.9)
≥ 30	166 (19.1)
Smoking
Smokers	246 (28.2)
Non-smokers	513 (58.9)
Ex-smokers	112 (12.8)
Appendectomy	224 (25.7)
Presence of co-morbidities
Charlson’s score	3 (2–4)
Charlson’s score > 3	220 (25.2)
Presence of any symptom	682 (78.3)
Cumulative symptom score^a	8 (2–13)
>7	441 (50.6)
Abdominal pain	2 (0–5)
>2	404 (46.4)
Bloating	2 (0–4)
>2	371 (42.6)
Constipation
Absent (0)	539 (62.0)
Mild (1 or 2)	123 (14.1)
Moderate to severe (> 2)	208 (23.9)
Diarrhea
Absent (0)	561 (64.4)
Mild (1 or 2)	111 (12.7)
Moderate to severe (> 2)	199 (22.9)
DICA classification
1	488 (56.0)
2	279 (32.1)
3	104 (11.9)
CODA score	10 (7–16)
Fecal calprotectin (μg/g)	25 (12–70)
> 90	151 (17.3)

Baseline parameter	Multivariable Cox PH model
Baseline parameter	HR (95% CI)	P-value
Constipation (per 1-VAS point increase)	1.15 (1.04–1.27)	0.004
Diarrhea (per 1-VAS point increase)	1.14 (1.03–1.26)	0.014
Sex (males vs. females)	1.51 (0.92–2.49)	0.104
Age (per 1-yr increase)	0.97 (0.95–0.99)	0.016

Name	Surname	Affiliation(s)
Marco	Astegiano	Division of Gastroenterology, “Molinette” University Hospital, Torino, Italy
Francesco	Bachetti	Department of Medicine and Surgery, Gastroenterology and Hepatology Unit, “Santa Maria Della Misericordia” University Hospital, University of Perugia, Perugia, Italy
Gianluca	Baldassarre	Digestive Endoscopy Unit, ULSS7 Alto Vicentino, Santorso (VI), Italy
Fabio	Baldi^†	Digestive Endoscopy Unit, Civil Hospital, Tarquinia (VT), Italy
Edoardo	Borsotti	Division of Gastroenterology, “San Donato” Hospital, San Donato Milanese (MI), Italy
Claudio	Cassieri	Division of Internal Medicine and Gastroenterology, “Cristo Re” Hospital, Rome, Italy
Alessia	Cazzato	Division of Gastroenterology, “Santa Caterina Novella” Hospital, Galatina (LE), Italy
Stefania	Chiri	Division of Gastroenterology, “Santa Caterina Novella” Hospital, Galatina (LE), Italy
Antonio	Ciccone	Division of Gastroenterology, Hepatology and Nutrition, San Salvatore Hospital, Department of Life, Health & Environmental Sciences, University of L'Aquila, L’Aquila, Italy
Alberto	Damiani	Service of Digestive Endoscopy, “Villa dei Pini” Home Care, Civitanova Marche (MC), Italy
Patrizia	De Colibus	Division of Gastroenterology, “T. Maresca” Hospital, Torre del Greco (NA), Italy
Roberto	Faggiani	Division of Gastroenterology, “S. Camillo” Hospital, Rome, Italy
Fabio	Finocchiaro	Division of Gastroenterology, “Molinette” University Hospital, Torino, Italy
Serafina	Fiorella	Division of Gastroenterology, “San Pio da Pietrelcina” Hospital, Vasto (CH), Italy
Francesca	Foschia	Territorial Gastroenterology Service, ASL Roma 2, Rome, Italy
Federica	Furfaro	Gastroenterology and Endoscopy, IRCCS Ospedale "San Raffaele" and University "Vita-Salute San Raffaele", Milan, Italy
Sara	Gallina	Division of Gastroenterology, “Belcolle” Hospital, Viterbo, Italy
Gian Marco	Giorgetti	Digestive Endoscopy and Nutritional Unit, “S. Eugenio” Hospital, Rome, Italy
Simona	Grad	2nd Medical Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
Giuseppe	Grande	Digestive Endoscopy Unit, “Sant’Agostino Estense” Hospital, Baggiovara (MO), Italy
Antonio	Grandolfo	Division of Gastroenterology, “S. Paolo” Hospital, Bari - Italy
Maria Antonia	Lai	Division of Gastroenterology, “Monserrato” University Hospital, University of Cagliari, Cagliari, Italy
Piera Giuseppina	Lecca	Division of Internal Medicine and Gastroenterology, “Cristo Re” Hospital, Rome, Italy
Loris Riccardo	Lopetuso	Division of Internal Medicine and Gastroenterology, IRCCS “A. Gemelli” Hospital, Fondazione Policlinico Gemelli, Catholic University, Rome, Italy; Department of Medicine and Ageing Sciences, ”G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy; Center for Advanced Studies and Technology (CAST), “G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy
Antonio	Penna	Territorial Gastroenterology Service, ASL Bari, Bari, Italy
Flavia	Pigo	Digestive Endoscopy Unit, “Sant’Agostino Estense” Hospital, Baggiovara (MO), Italy
Piero	Portincasa	Internal Medicine Unit, “A. Murri” Medical Clinic, Policlinico University Hospital, Bari, Italy
Giannenrico	Rizzatti	Division of Internal Medicine and Gastroenterology, IRCCS “A. Gemelli” Hospital, Fondazione Policlinico Gemelli, Catholic University, Rome, Italy
Giovanni Luca	Rizzo	Division of Gastroenterology, “Perrino” Hospital, Brindisi, Italy
Stefano	Rodino	Division of Gastroenterology, “Pugliese-Ciaccio” Hospital, Catanzaro, Italy
Stefania	Scanni	Territorial Gastroenterology Service, ASL Roma 2, Rome, Italy
Luigi	Schiffino	Division of Gastroenterology and Surgical Endoscopy, “Grassi” Hospital, Ostia, Rome, Italy
Erasmo	Spaziani	Department of Surgery, “Sapienza” University of Rome-Polo Pontino, Terracina (LT), Italy
Antonino	Tesoriere	Digestive Endoscopy Unit, Civil Hospital, Tarquinia (VT), Italy
Riccardo	Urgesi	Division of Gastroenterology and Digestive Endoscopy “S. Giovanni-Addolorata” Hospital, Rome, Italy
Paolo	Usai	Division of Gastroenterology, “Monserrato” University Hospital, University of Cagliari, Cagliari, Italy

Table 1. Baseline Demographic and Clinical Characteristics of the Study Population

Values are presented as median (interquartile range) or number (%).

The cumulative symptom score ranges from 0 to 40 points. It is obtained by adding the points regarding abdominal pain, meteorism, constipation, and diarrhea as measured on a 10-point visual analog scale.

DICA, Diverticular Inflammation and Complication Assessment; CODA, Combined Overview on Diverticular Assessment.

Table 2. Effect of Constipation and Diarrhea on the Risk of Acute Diverticulitis: Time-to-Event Analysis

PH, proportional-hazard; HR, hazard ratio; CI, confidence interval; VAS, visual analog scale.

†

The co-author Fabio Baldi, MD deceased.