Alimentary Pharmacology and Therapeutics
Review article: the pathogenesis and management of acute colonic diverticulitis D. J. Humes & R. C. Spiller
Nottingham Digestive Diseases Centre and Biomedical Research Unit, Nottingham University Hospital NHS Trust, Nottingham, UK.
Correspondence to: Dr D. J. Humes, Nottingham Digestive Disease Centre and Biomedical Research Unit, Department of Surgery, QMC Campus, E Floor, West Block, Nottingham University Hospital NHS Trust, Derby Road Nottingham NG7 2UH, UK. E-mail: [email protected]
Publication data Submitted 28 June 2013 First decision 18 July 2013 Resubmitted 9 December 2013 Accepted 9 December 2013 EV Pub Online 6 January 2014 This commissioned review article was subject to full peer-review and the authors received an honorarium from Wiley, on behalf of AP&T.
SUMMARY Background Acute diverticulitis, defined as acute inflammation associated with a colonic diverticulum, is a common emergency presentation managed by both surgeons and physicians. There have been advances in both the medical and the surgical treatments offered to patients in recent years. Aim To review the current understanding of the aetiology and treatment of acute diverticulitis. Methods A search of PubMed and Medline databases was performed to identify articles relevant to the aetiology, pathogenesis and management of acute diverticulitis. Results There are 75 hospital admissions per year for acute diverticulitis per 100 000 of the population in the United States. Recent reports suggest a 26% increase in admissions over a 7-year period. Factors predisposing to the development of acute diverticulitis include obesity, smoking, diet, lack of physical activity and medication use such as aspirin and nonsteroidal anti-inflammatory drugs. The condition is associated with a low mortality of about 1% following medical therapy, rising to 4% in-hospital mortality in those requiring surgery. There is limited evidence on the efficacy of individual antibiotic regimens, and antibiotic treatment may not be required in all patients. The rates of recurrence reported for patients with acute diverticulitis following medical management vary from 13% to 36%. The surgical management of those patients who fail medical treatment has moved towards a laparoscopic nonresectional approach; however, the evidence supporting this is limited. Conclusions Further high-quality randomised controlled trials are required of both medical and surgical treatments in patients with acute diverticulitis, if management is to be evidence-based. Aliment Pharmacol Ther 2014; 39: 359–370
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12596
359
D. J. Humes and R. C. Spiller INTRODUCTION Emergency hospital admissions with acute diverticulitis are increasing which, given the age and comorbidity of the patients’ presenting, place a significant burden on health care resources.1–3 There are few evidence-based guidelines for the management of these patients, but given the ageing population and the expected continued rise in disease burden, strategies to reduce admission and tailor treatment are required if health care resources are not to be over burdened by this group.4 In recent years, there have been changes in the demographics of the patients presenting along with challenges to the long-standing held views on the medical and surgical management of these patients. This article aimed to review the pathogenesis of acute diverticulitis and detail the current evidence with regard to the treatment of patients presenting with acute diverticulitis and their subsequent management. METHODS Search strategy An electronic literature search was conducted using PubMed and Medline as primary sources. No time limits were specified up to the date of the search (November 2013). A comprehensive search was performed using the following search terms: acute diverticulitis, aetiology, pathogenesis, recurrence, treatment, management, antibiotics, surgery and pathology. Logical combinations of these and related terms were used to maximise the sensitivity of the search. The search was restricted to articles involving humans and those in the English language (or with an English abstract). Selection process This was not a systematic review. Following identification of relevant titles, the abstracts of these articles were read to decide if the study was eligible. The full text article was retrieved when the title and/or abstract appeared to meet the pre-defined eligibility criteria. A manual cross-reference search of bibliographies was carried out to identify articles missed in the computerised search. Articles were included in the review if they presented relevant data that would improve the readers understanding of this common condition and presented relevant data with regard to the management of patients with acute diverticulitis. Therefore, there was a focus on clinical reviews, randomised controlled trials, recent epidemiological studies and current National guidelines. 360
Epidemiology and pathogenesis The true incidence of acute diverticulitis is unknown as studies have only focused on patients admitted to hospital and so underestimate the true burden of disease. Studies from the United States of America have used routinely collected data from the Nationwide Inpatient Sample (NIS) database to report on the occurrence of acute diverticulitis associated with an emergency hospital admission.1, 3, 5 The first of these studies reported a 26% increase in admissions from 1998 to 2005 (0.59–0.71 per 1000 population from 1998 to 2005)1 with the greatest increase in those of a younger age, although they still represented a small proportion of the total admissions. A further study of the NIS from 2002 to 2007 reported a 9.5% year on year rise in hospitalisation for acute diverticulitis with 85% of these emergency admissions being treated medically.3 A geographical difference in incidence rates was noted with the Northeast having the greatest percentage increase in admissions and the West having both the lowest rates of hospitalisation and the smallest percentage increase in admissions.5 These increases in admissions have been mirrored by increasing rates of hospitalisation in the UK as reported from Hospital Episode Statics data, although these studies are limited by coding and cannot report overall rates of admission for acute diverticulitis.6, 7 It would appear, therefore, that the rates of admission are increasing. Although changes in coding and the use of diagnostic tests such as computed tomography may contribute to these changing patterns, this is unlikely given the differing patterns in admission occurring across age groups. The burden on patients seen in primary care is unknown; however, it is likely that many patients, particularly those with no systemic inflammatory response and a known diagnosis of diverticular disease, are treated in primary care for episodes of left iliac fossa pain and hence never recorded in admission databases. Studies on the occurrence of acute diverticulitis in the community are therefore needed to detail the incidence of the condition and accurately define the health burden for both primary and secondary care. A further burden is associated with recurrent episodes of acute diverticulitis; however, data on recurrence rates are limited. More than 40 years ago, Parks reported a 26% (78/297) recurrence rate for medically treated acute diverticulitis with 46% (36/78) occurring in the first year after the initial attack.8 More recently, a 5-year recurrence of 36% (95% CI, 31.4–40.6%) was reported in a retrospective study of 672 patients admitted with acute diverticulitis.9 Of 221 patients treated medically following Aliment Pharmacol Ther 2014; 39: 359-370 ª 2014 John Wiley & Sons Ltd
Review: diverticulitis pathogenesis and management a first admission with acute diverticulitis, overall readmission was 20.8% (46/221).10 A further study of 502 patients from New Zealand reported a recurrence rate of 18.8% (60/320) with a median follow-up of 101 months and no increase in mortality related to recurrent episodes.11 These studies are all small and have varying diagnostic criteria for acute diverticulitis and its recurrence. A population-based study of 314 patients treated non-operatively for acute diverticulitis from California reported a recurrence rate of 13.3% with a median follow-up of 8.9 years with age >50 years associated with a lower recurrence rate and those with higher comorbidity having the greatest recurrent rate.12 In a prospective study of 280 patients with proven uncomplicated acute diverticulitis with a median follow-up of 24 months, 46 (16.4%) experienced a second episode of acute diverticulitis with just four patients requiring surgery.13 In a recent meta-analysis of 23 078 patients from eight studies, patients under the age of 50 years were more likely to have a recurrent attack (RR 1.73; 95% CI 1.40–2.13) than those older than 50 years.14 The rates of recurrence reported for patients with acute diverticulitis following medical management vary from 13.3% to 36% depending on the population studied and the length of follow-up applied. These studies have only detailed readmission with acute diverticulitis to hospital, so there are no estimates of the burden that recurrent episodes place on primary care where most present. An understanding of the rates of recurrence and definitions of recurrence is required if appropriate trials are to be designed detailing possible preventative strategies. The underlying pathological mechanisms that cause the formation of colonic diverticula remain unclear.15, 16 There are likely to be complex interactions among diet, colonic microbiota, genetic factors, colonic motility and structure that result in their formation over time. The prevalence of the condition in autopsy studies increases steadily with age in Northern European populations17 and shows strong environmental influences being uncommon in immigrants from Africa and Asia, but steadily increasing with the number of years residence in a high incidence area.18 Heritability is calculated to be around 40%19 and there are a number of rare disorders of collagen19–21 and elastin,20 which are associated with complicated diverticular disease at an early age. However, as with inflammatory bowel disease, there are probably many genes involved and most diverticulosis is likely to be the result of small effects from many genes. Neural degeneration with age may also contribute as several studies suggest reduction in neurones in the myenAliment Pharmacol Ther 2014; 39: 359-370 ª 2014 John Wiley & Sons Ltd
teric plexus22 and decreased myenteric glial cells and interstitial cells of cajal.23 Denervation hypersensitivity has also been reported24 and these abnormalities of enteric nerves might lead to inco-ordinate contractions and high pressure producing diverticulosis, but this is highly speculative given the lack of good animal models of the condition. The associated muscular hypertrophy and altered enteric nerves25 may result from remodelling after acute inflammation, which is known from many animal studies to be associated with muscular hypertrophy, abnormal motility,26 visceral hypersensitivity and altered neurochemical coding.27, 28 Such changes may account for the common experience of the development of recurrent abdominal pain and disturbed bowel habit following acute diverticulitis29 and the finding of visceral hypersensitivity in patients with symptomatic diverticular disease.30, 31 The development of inflammation in these diverticula results in acute diverticulitis. It has been suggested that in the same way, obstruction by faecal material causes appendicitis, that faecal matter becomes trapped in the diverticula and as a result, low-grade inflammation develops due to abrasion of the mucosa, allowing access of faecal microbiota to the lamina propria, leading to acute inflammation of the mucosa, which usually begins at the apex of the sac.32, 33 This can be associated with acute inflammation of the mesenteric and pericolic fat with the formation of a diverticular abscess. Another postulated mechanism for the development of acute diverticulitis is a micro-perforation at the fundus of the diverticulum leading to inflammation.34 Peritoneal involvement is painful and invariably leads to a systemic response with fever and leucocytosis. Progression to complicated disease with fistula, abscess or perforation is seen in only a minority of patients and there is evidence that the majority of the patients presenting with these complications have not suffered prior episodes of acute diverticulitis, suggesting that these may well represent separate clinical entities.35, 36 There is evidence that those patients with uncomplicated disease without signs of sepsis may resolve without any treatment, possibly due to the inflammatory exudate causing expulsion of the contents of the diverticulum into the colonic lumen leading to resolution of inflammation.37 Ultrasonography has shown, in selected cases, the sequence of fecolith obstruction, pus formation, followed by expulsion of the fecolith and spontaneous resolution.38 A more detailed understanding of the pathogenesis of the condition and its natural history may allow us to adopt treatment strategies directed at individual patients. It is likely that future research in this area will focus on the role of the 361
D. J. Humes and R. C. Spiller gut microbiota in the development of inflammation, but as yet relevant data are lacking. Figure 1 outlines the pathogenesis of diverticulosis and acute diverticulitis. Other factors have been implicated in the pathogenesis of the condition. A low-fibre diet has been suggested as a causative factor in the development of diverticulosis; however, the role of diet remains unclear in the development of acute diverticulitis. A record linkage study using data from the EPIC cohort has reported a decrease in hospital admissions for diverticular disease in vegetarians with high-fibre diets. This decrease in admissions may be the result of a healthier lifestyle or because fibre reduces the risk of acute diverticulitis.39 The consumption of nuts, popcorn and corn had been advised against in patients with known diverticular disease.40 A recent report from the Health Professionals Follow Study found no relationship between consumption of corn, nuts or popcorn and the development of diverticulitis.41 An increased risk of acute diverticulitis has been reported from a Danish cohort of in-patient alcoholic patients who were followed up with record linkage from 1977 to 1993.42 The study reported a 2.0- and 2.9-fold increase in relative risk for men and women, respectively, following diagnosis of alcoholism. The authors speculated that the association could relate to the immunosuppressive effects of alcohol consumption. However, this association could also be due to an ascertainment bias due to increased investigation in alcoholics requiring hospital admission compared with the general population. A BMI of greater than 30 kg/m2 increased the relative risk of an episode of acute diverticulitis by 1.78 (95% CI, 1.08– 2.94) compared with a normal BMI in a cohort study of male American Health Care Professionals.43 Waist
circumference and waist-to-hip ratio were also independently associated with this. The mechanism responsible for this increased risk is unknown, but may include the pro-inflammatory nature of adipose tissue, which secretes cytokines that may promote the inflammatory response. Physical activity was reported to decrease the risk of developing diverticulitis in the same cohort by 25% (RR 0.75, 95% CI 0.58–0.95) when comparing those in the highest quintile of physical activity with those in the lowest.44 Smoking was reported to be associated with a threefold increased risk of diverticular complications including severe diverticulitis in a small retrospective study.45 A further study of patients from Finland reported an increased risk of recurrent episodes of acute diverticulitis in smokers following surgical intervention.46 Current users of aspirin and non-aspirin, nonsteroidal anti-inflammatory drugs are at a 1.25- and 1.7-fold increased risk of developing acute diverticulitis compared with non-users.47 It was postulated that this increased risk was due to mucosal damage resulting in impaired barrier function of the colonic mucosa allowing translocation of bacteria, which provoke inflammation.
Clinical presentation Patients typically present with left lower quadrant pain, although those with a large redundant sigmoid colon, may have suprapubic or right-sided pain if the sigmoid colon lies to that side. The patient may have diffuse abdominal pain indicating complicated disease such as perforation. The pain can be constant or intermittent and may be associated with nausea and vomiting in up to a third of patients.48 Change in bowel habit can occur with both constipation and diarrhoea, the latter being
Environmental influences Diet, microbiota
Genetic predisposition Weakening of Colonic wall
Neural degeneration Altered receptor sensitivity Circular/longitudinal muscle thickening
Elastosis
A g e i n g
Development of diverticulosis Faecolith impaction Micro perforation Environmental influences Diverticulitis Post inflammatory hypersensitivity 362
Chronic symptoms Pain, diarrhoea, constipation
Figure 1 | The possible pathogenesis of both diverticulosis and acute diverticulitis. Aliment Pharmacol Ther 2014; 39: 359-370 ª 2014 John Wiley & Sons Ltd
Review: diverticulitis pathogenesis and management more common in a recent review of presenting symptoms in patients to the emergency department with acute diverticulitis; however, the patient may rarely present with absolute constipation due to an underlying obstruction.35 The patient may report dysuria secondary to irritation of the bladder by the inflamed segment of colon. The differential diagnosis of acute colonic diverticulitis is listed in Table 1. On examination, the patient may be tender in the left lower quadrant with localised guarding and rigidity. Severe disease associated with peritonitis may present with a rigid board-like abdomen. Rarely, a mass may be palpable in the left iliac fossa. Bowel sounds may be depressed or increased in those patients with associated obstruction with a stricture. Rectal examination may be normal or elicit tenderness in the case of a pelvic abscess. Patients may have a fever and be tachycardic.
INVESTIGATIONS An algorithm for the investigation and management of patient with acute diverticulitis based on current clinical practice guidelines is shown in Figure 2. Bed side investigations should include a urine analysis to exclude urinary tract infection and pregnancy in women of child-bearing age, remembering that blood and protein in the urine may reflect bladder/ureter inflammation secondary to diverticulitis. Blood tests should include a full
Table 1 | The differential diagnosis of acute diverticulitis Gastrointestinal Acute diverticulitis Infective colitis Inflammatory bowel disease Ischaemic bowel Volvulus Malignancy Constipation Omental infarction Epiploic appendagitis Genitourinary Urinary tract infection Renal colic Prostatitis Gynaecological Ovarian cysts Ectopic Salpingitis Other Hernia Psoas abscess Retroperitoneal haemorrhage Aliment Pharmacol Ther 2014; 39: 359-370 ª 2014 John Wiley & Sons Ltd
blood count, urea and electrolytes along with a C-reactive protein and amylase or lipase (as local policy dictates). The clinical triad of left lower quadrant pain, fever and leucocytosis is often quoted in the diagnosis of acute diverticulitis; however, precise data on its accuracy are lacking. A recent retrospective study using HMO records in California found leukocytosis in 58.5% and temperature >37.5 °C in 30.1% of patients presenting to the emergency department with acute diverticulitis. However, the triad of abdominal pain, fever and leukocytosis was found in only 47% of those with severe findings on CT (abscess, perforation),35 indicating an unacceptable sensitivity, despite specificity of 95.2%. It is currently recommended that either CT or US scanning (depending on local expertise) should be undertaken within 72 h of admission to confirm the clinical diagnosis of acute diverticulitis and exclude any associated complications.49, 50 This position has been challenged and authors have attempted to identify severe cases that may benefit from imaging and reduce patient radiation exposure and health care costs in those with uncomplicated diverticulitis.48 The Longstreth study found severe CT findings in just 3.8%, of those with lower rather than generalised abdominal pain and no fever or leukocytosis, suggesting that for such patients, a wait and see approach might be cost effective without CT. The optimal imaging modality for patients with acute diverticulitis was recently the subject of a Cochrane review, which commented on how few high-quality studies there were.51 The review reported that ultrasound had a sensitivity of 84–99%, but a specificity of as low as 57% and as high as 100%, suggesting considerable local variability in expertise. Typical ultrasound appearances are of a thickened loop of bowel with a target-like appearance.52 The same review found a wide range of sensitivities for CT varying from 65% to 97% with a specificity of 77– 100%. The typical findings on CT are pericolonic fat stranding, bowel wall thickening and diverticular. Additional findings may include abscess, free fluid, free air, an inflamed diverticulum or the arrowhead sign in which contrast material shows an arrowhead configuration at the ostia of an inflamed diverticulum (Figure 3 shows an inflamed sigmoid diverticular segment with associated abscess).52 Studies comparing the two modalities are limited and the review concluded that it was difficult to draw firm conclusions, especially as the quality of CT has improved so much recently. The recent ACPGBI position statement concluded that the choice between the two modalities should be made on local expertise.49 The recent American College of Radiology Guidelines 363
D. J. Humes and R. C. Spiller
Bed side Urine dip Urine pregnancy test (child bearing age)
Presentation with suspected acute diverticulitis
Radiological Erect chest x-ray (if perforation suspected) Abdominal x-ray (if obstruction suspected) CT/US scan accoring to local expertise (all patients with a new diagnosis or those with suspected complications)
Admit Analgesia Commence treatment with broad spectrum antibiotics via local policy Discharge Analgesia Commence oral antibiotics via local policy
Follow up Colonoscopy at 8 weeks to exclude incidental cancer in new diagnosis No evidence of effective measures of prevention of recurrence
Laboratory Full blood Count Renal Function Creactive protein Amylase
Figure 2 | Investigation and treatment algorithm for patients presenting with suspected acute diverticulitis based on current guidelines.49, 50
suggested CT in the first instance as US was limited by operator expertise.52 Ultrasound, however, may have a role in premenopausal women and the young to reduce radiation exposure.53 Barium enema sensitivity varies from 29% to 93% with specificity of 50–100%, but its inability to visualise extra-luminal complications means that it is no longer used acutely.
Figure 3 | CT scan of acute sigmoid diverticulitis with associated abscess formation (white arrow), which required surgical resection. 364
RISK STRATIFICATION The majority (70–80%) of patients with acute diverticulitis can be managed without surgical intervention. There has been interest in predicting those patients who settle quickly on medical therapy and those that will require prolonged admission to attempt to reduce hospital stay and therefore health care burden. A retrospective review of 145 patients presenting to a University hospital identified reduction in leucocyte count and temperature over the 48 h from admission to be predictive of early discharge in patients with CT-confirmed acute diverticulitis receiving intravenous and then oral antibiotics.54 Along with limiting hospital stay, there have been attempts to better define those patients who may be treated at home. A study of out-patient management of 137 patients used ultrasound to confirm the diagnosis of acute diverticulitis and grade severity as mild to moderate. The study found that patients 2 cm could be successfully treated in the community with oral antibiotics and hydration with an out-patient review at day 4 and day 7. The success rate in such patients, who represented 55% of the total, was 97% (68/70) with an 80% reduction in treatment cost.55 A further study has evaluated the treatment of patients with uncomplicated diverticulitis in patients with comorbidity at home and found that after an 18-h hospital stay, 24 patients with comorbidity were successfully treated at home by a dedicated Hospital at Home team.56 A study of 693 patients who had acute diverticulitis Aliment Pharmacol Ther 2014; 39: 359-370 ª 2014 John Wiley & Sons Ltd
Review: diverticulitis pathogenesis and management confirmed on CT and were subsequently discharged home from the emergency room found only a 6% treatment failure rate defined as return to the emergency room or admission with acute diverticulitis within 60 days.57 Female patients and those with free fluid on CT were at greatest risk of treatment failure. A further study of 132 patients with CT proven uncomplicated acute diverticulitis randomised treatment in the community or hospital admission demonstrated no difference in failure rates of treatment between the two groups, but found lower costs in the community treated group.58 The use of mesalazine in patients with uncomplicated symptomatic diverticular disease has been proposed with a recent randomised trial reporting a nonsignificant reduction in median lower abdominal pain in the mesalazine group.59 Reliable identification of patients with acute diverticulitis who may be safely treated in the community is required and further research is needed in this area to maximise the potential benefits of avoiding hospital admission for patients and to reduce health care costs.
TREATMENT Conservative/Medical There has been increased interest in treating patients with acute diverticulitis conservatively. Addressing known risk factors such as obesity, lack of physical activity, alcohol and smoking in theory might reduce the risk of developing acute diverticulitis in an individual within known diverticulosis or reduce recurrent attacks,
although there is as yet no direct evidence to support this idea.60 Over recent years, there has been a challenge to the traditional treatment of acute diverticulitis with antibiotics and admission to hospital. Conservative treatment of acute diverticulitis normally includes bowel rest with intravenous fluids and antibiotics with appropriate analgesia. Until recently, there was a lack of randomised controlled trials that compared antibiotic treatment with no antibiotic treatment. Trials had largely focused on comparison of different antibiotic regimes.61, 62 An initial publication of a retrospective review of 311 patients admitted to a single Hospital in Sweden demonstrated that managing mild acute diverticulitis without antibiotics, but merely bowel rest and observation lead to no increase in adverse events compared with those patients treated with antibiotics who were generally sicker with more severe CT grading.37 These findings encouraged a randomised controlled trial of antibiotics in patients with acute uncomplicated acute diverticulitis from Sweden, which reported no difference in complications such as abscess or perforation between those treated with or without antibiotics with a median length of stay in both groups of 3 days.63 This study, however, was criticised for excluding patients with sepsis (though no definition of sepsis was provided) and for problems with possible selection bias, given that not all patients eligible for the study were recorded. It remains to be seen if these results are generalisable. Table 2 summarises the trials to date detailing the role of antibiotics in the treatment of patients with acute diverticulitis. Given the rise in noso-
Table 2 | Summary of randomised trials of antibiotic treatment in patients with acute diverticulitis Author Kellum et al.
Trial Patients design (n) Diagnosis RCT
51
Ridgway RCT et al.
80
Chabok et al.
623
RCT
Duration
Endpoint
Significance
Clinical cure NS Clinical diagnosis of 30 intravenous cefoxitin (1–2 g every acute diverticulitis 6 h) 21 intravenous gentamicin (1.7 mg/kg loading dose then 1.0–1.4 mg/kg every 8 h) plus clindamycin (2400–27 000 mg/day in three or four divided doses) NS Clinical diagnosis of 41 oral ciprofloxacin (500 mg b.d.) and Abdominal tenderness acute diverticulitis metronidazole (400 mg t.d.s.) vs. 38 at day 3 IV ciprofloxacin (400 mg b.d.) and metronidazole (500 mg t.d.s.) Development of NS CT verified 309 no antibiotics vs. 314 antibiotics a complication uncomplicated (given according to local policy (perforation/abscess) acute diverticulitis second or third generation cephlasporin and metronidazole or carbopenam or piperacillin
Aliment Pharmacol Ther 2014; 39: 359-370 ª 2014 John Wiley & Sons Ltd
365
D. J. Humes and R. C. Spiller comial infections particularly Clostridium difficile associated colitis and antibiotic resistance, it would seem desirable to be able to restrict the use of antibiotics in this large patient group to only those that may benefit. Further trials in this area are required and we await the result of the DIABOLO trial,64 which is a randomised trial of 48 h of intravenous antibiotics, admission to hospital and bowel rest vs. a liberal strategy of no antibiotics and admission if only clinically indicated for radiologically proven, uncomplicated, acute diverticulitis. The primary endpoint of the study is full recovery within 6 months. It is hoped that this will clarify the management of this group of patients with radiologically proven acute diverticulitis. There has been growing interest in the role of antibiotics, 5-aminosalicylates and probiotics in the prevention of recurrent attacks of acute diverticulitis. Studies to date have generally been of poor methodological quality and so deriving clear guidance from these is difficult. Several systematic reviews have concluded that the evidence for these interventions is weak and further high-quality randomised controlled trials are required to prove efficacy.65–67 The most recently published RCT in this area compared mesalazine, or mesalazine plus Bifidobacterium infantis 35624 for 12 weeks and followed up for nine additional months. Global symptom scores were assessed over the 52 weeks of follow-up.68 No statistical difference in symptom scores was found; however, those receiving mesalazine did have a consistent trend in reducing symptoms. The addition of a probiotic failed to increase the efficacy of mesalazine. Recent studies suggesting that mesalazine may be beneficial in IBS69 complicate interpretation of diverticular studies as it may be hard to distinguish uncomplicated diverticular disease from IBS and this may explain some of the benefit reported with mesalazine in previous studies. More recently, a large well-designed RCT examined the effect of 48 weeks of mesalazine 3 g daily vs. placebo in patients with a recent (
Review article: the pathogenesis and management of acute colonic diverticulitis D. J. Humes & R. C. Spiller
Nottingham Digestive Diseases Centre and Biomedical Research Unit, Nottingham University Hospital NHS Trust, Nottingham, UK.
Correspondence to: Dr D. J. Humes, Nottingham Digestive Disease Centre and Biomedical Research Unit, Department of Surgery, QMC Campus, E Floor, West Block, Nottingham University Hospital NHS Trust, Derby Road Nottingham NG7 2UH, UK. E-mail: [email protected]
Publication data Submitted 28 June 2013 First decision 18 July 2013 Resubmitted 9 December 2013 Accepted 9 December 2013 EV Pub Online 6 January 2014 This commissioned review article was subject to full peer-review and the authors received an honorarium from Wiley, on behalf of AP&T.
SUMMARY Background Acute diverticulitis, defined as acute inflammation associated with a colonic diverticulum, is a common emergency presentation managed by both surgeons and physicians. There have been advances in both the medical and the surgical treatments offered to patients in recent years. Aim To review the current understanding of the aetiology and treatment of acute diverticulitis. Methods A search of PubMed and Medline databases was performed to identify articles relevant to the aetiology, pathogenesis and management of acute diverticulitis. Results There are 75 hospital admissions per year for acute diverticulitis per 100 000 of the population in the United States. Recent reports suggest a 26% increase in admissions over a 7-year period. Factors predisposing to the development of acute diverticulitis include obesity, smoking, diet, lack of physical activity and medication use such as aspirin and nonsteroidal anti-inflammatory drugs. The condition is associated with a low mortality of about 1% following medical therapy, rising to 4% in-hospital mortality in those requiring surgery. There is limited evidence on the efficacy of individual antibiotic regimens, and antibiotic treatment may not be required in all patients. The rates of recurrence reported for patients with acute diverticulitis following medical management vary from 13% to 36%. The surgical management of those patients who fail medical treatment has moved towards a laparoscopic nonresectional approach; however, the evidence supporting this is limited. Conclusions Further high-quality randomised controlled trials are required of both medical and surgical treatments in patients with acute diverticulitis, if management is to be evidence-based. Aliment Pharmacol Ther 2014; 39: 359–370
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12596
359
D. J. Humes and R. C. Spiller INTRODUCTION Emergency hospital admissions with acute diverticulitis are increasing which, given the age and comorbidity of the patients’ presenting, place a significant burden on health care resources.1–3 There are few evidence-based guidelines for the management of these patients, but given the ageing population and the expected continued rise in disease burden, strategies to reduce admission and tailor treatment are required if health care resources are not to be over burdened by this group.4 In recent years, there have been changes in the demographics of the patients presenting along with challenges to the long-standing held views on the medical and surgical management of these patients. This article aimed to review the pathogenesis of acute diverticulitis and detail the current evidence with regard to the treatment of patients presenting with acute diverticulitis and their subsequent management. METHODS Search strategy An electronic literature search was conducted using PubMed and Medline as primary sources. No time limits were specified up to the date of the search (November 2013). A comprehensive search was performed using the following search terms: acute diverticulitis, aetiology, pathogenesis, recurrence, treatment, management, antibiotics, surgery and pathology. Logical combinations of these and related terms were used to maximise the sensitivity of the search. The search was restricted to articles involving humans and those in the English language (or with an English abstract). Selection process This was not a systematic review. Following identification of relevant titles, the abstracts of these articles were read to decide if the study was eligible. The full text article was retrieved when the title and/or abstract appeared to meet the pre-defined eligibility criteria. A manual cross-reference search of bibliographies was carried out to identify articles missed in the computerised search. Articles were included in the review if they presented relevant data that would improve the readers understanding of this common condition and presented relevant data with regard to the management of patients with acute diverticulitis. Therefore, there was a focus on clinical reviews, randomised controlled trials, recent epidemiological studies and current National guidelines. 360
Epidemiology and pathogenesis The true incidence of acute diverticulitis is unknown as studies have only focused on patients admitted to hospital and so underestimate the true burden of disease. Studies from the United States of America have used routinely collected data from the Nationwide Inpatient Sample (NIS) database to report on the occurrence of acute diverticulitis associated with an emergency hospital admission.1, 3, 5 The first of these studies reported a 26% increase in admissions from 1998 to 2005 (0.59–0.71 per 1000 population from 1998 to 2005)1 with the greatest increase in those of a younger age, although they still represented a small proportion of the total admissions. A further study of the NIS from 2002 to 2007 reported a 9.5% year on year rise in hospitalisation for acute diverticulitis with 85% of these emergency admissions being treated medically.3 A geographical difference in incidence rates was noted with the Northeast having the greatest percentage increase in admissions and the West having both the lowest rates of hospitalisation and the smallest percentage increase in admissions.5 These increases in admissions have been mirrored by increasing rates of hospitalisation in the UK as reported from Hospital Episode Statics data, although these studies are limited by coding and cannot report overall rates of admission for acute diverticulitis.6, 7 It would appear, therefore, that the rates of admission are increasing. Although changes in coding and the use of diagnostic tests such as computed tomography may contribute to these changing patterns, this is unlikely given the differing patterns in admission occurring across age groups. The burden on patients seen in primary care is unknown; however, it is likely that many patients, particularly those with no systemic inflammatory response and a known diagnosis of diverticular disease, are treated in primary care for episodes of left iliac fossa pain and hence never recorded in admission databases. Studies on the occurrence of acute diverticulitis in the community are therefore needed to detail the incidence of the condition and accurately define the health burden for both primary and secondary care. A further burden is associated with recurrent episodes of acute diverticulitis; however, data on recurrence rates are limited. More than 40 years ago, Parks reported a 26% (78/297) recurrence rate for medically treated acute diverticulitis with 46% (36/78) occurring in the first year after the initial attack.8 More recently, a 5-year recurrence of 36% (95% CI, 31.4–40.6%) was reported in a retrospective study of 672 patients admitted with acute diverticulitis.9 Of 221 patients treated medically following Aliment Pharmacol Ther 2014; 39: 359-370 ª 2014 John Wiley & Sons Ltd
Review: diverticulitis pathogenesis and management a first admission with acute diverticulitis, overall readmission was 20.8% (46/221).10 A further study of 502 patients from New Zealand reported a recurrence rate of 18.8% (60/320) with a median follow-up of 101 months and no increase in mortality related to recurrent episodes.11 These studies are all small and have varying diagnostic criteria for acute diverticulitis and its recurrence. A population-based study of 314 patients treated non-operatively for acute diverticulitis from California reported a recurrence rate of 13.3% with a median follow-up of 8.9 years with age >50 years associated with a lower recurrence rate and those with higher comorbidity having the greatest recurrent rate.12 In a prospective study of 280 patients with proven uncomplicated acute diverticulitis with a median follow-up of 24 months, 46 (16.4%) experienced a second episode of acute diverticulitis with just four patients requiring surgery.13 In a recent meta-analysis of 23 078 patients from eight studies, patients under the age of 50 years were more likely to have a recurrent attack (RR 1.73; 95% CI 1.40–2.13) than those older than 50 years.14 The rates of recurrence reported for patients with acute diverticulitis following medical management vary from 13.3% to 36% depending on the population studied and the length of follow-up applied. These studies have only detailed readmission with acute diverticulitis to hospital, so there are no estimates of the burden that recurrent episodes place on primary care where most present. An understanding of the rates of recurrence and definitions of recurrence is required if appropriate trials are to be designed detailing possible preventative strategies. The underlying pathological mechanisms that cause the formation of colonic diverticula remain unclear.15, 16 There are likely to be complex interactions among diet, colonic microbiota, genetic factors, colonic motility and structure that result in their formation over time. The prevalence of the condition in autopsy studies increases steadily with age in Northern European populations17 and shows strong environmental influences being uncommon in immigrants from Africa and Asia, but steadily increasing with the number of years residence in a high incidence area.18 Heritability is calculated to be around 40%19 and there are a number of rare disorders of collagen19–21 and elastin,20 which are associated with complicated diverticular disease at an early age. However, as with inflammatory bowel disease, there are probably many genes involved and most diverticulosis is likely to be the result of small effects from many genes. Neural degeneration with age may also contribute as several studies suggest reduction in neurones in the myenAliment Pharmacol Ther 2014; 39: 359-370 ª 2014 John Wiley & Sons Ltd
teric plexus22 and decreased myenteric glial cells and interstitial cells of cajal.23 Denervation hypersensitivity has also been reported24 and these abnormalities of enteric nerves might lead to inco-ordinate contractions and high pressure producing diverticulosis, but this is highly speculative given the lack of good animal models of the condition. The associated muscular hypertrophy and altered enteric nerves25 may result from remodelling after acute inflammation, which is known from many animal studies to be associated with muscular hypertrophy, abnormal motility,26 visceral hypersensitivity and altered neurochemical coding.27, 28 Such changes may account for the common experience of the development of recurrent abdominal pain and disturbed bowel habit following acute diverticulitis29 and the finding of visceral hypersensitivity in patients with symptomatic diverticular disease.30, 31 The development of inflammation in these diverticula results in acute diverticulitis. It has been suggested that in the same way, obstruction by faecal material causes appendicitis, that faecal matter becomes trapped in the diverticula and as a result, low-grade inflammation develops due to abrasion of the mucosa, allowing access of faecal microbiota to the lamina propria, leading to acute inflammation of the mucosa, which usually begins at the apex of the sac.32, 33 This can be associated with acute inflammation of the mesenteric and pericolic fat with the formation of a diverticular abscess. Another postulated mechanism for the development of acute diverticulitis is a micro-perforation at the fundus of the diverticulum leading to inflammation.34 Peritoneal involvement is painful and invariably leads to a systemic response with fever and leucocytosis. Progression to complicated disease with fistula, abscess or perforation is seen in only a minority of patients and there is evidence that the majority of the patients presenting with these complications have not suffered prior episodes of acute diverticulitis, suggesting that these may well represent separate clinical entities.35, 36 There is evidence that those patients with uncomplicated disease without signs of sepsis may resolve without any treatment, possibly due to the inflammatory exudate causing expulsion of the contents of the diverticulum into the colonic lumen leading to resolution of inflammation.37 Ultrasonography has shown, in selected cases, the sequence of fecolith obstruction, pus formation, followed by expulsion of the fecolith and spontaneous resolution.38 A more detailed understanding of the pathogenesis of the condition and its natural history may allow us to adopt treatment strategies directed at individual patients. It is likely that future research in this area will focus on the role of the 361
D. J. Humes and R. C. Spiller gut microbiota in the development of inflammation, but as yet relevant data are lacking. Figure 1 outlines the pathogenesis of diverticulosis and acute diverticulitis. Other factors have been implicated in the pathogenesis of the condition. A low-fibre diet has been suggested as a causative factor in the development of diverticulosis; however, the role of diet remains unclear in the development of acute diverticulitis. A record linkage study using data from the EPIC cohort has reported a decrease in hospital admissions for diverticular disease in vegetarians with high-fibre diets. This decrease in admissions may be the result of a healthier lifestyle or because fibre reduces the risk of acute diverticulitis.39 The consumption of nuts, popcorn and corn had been advised against in patients with known diverticular disease.40 A recent report from the Health Professionals Follow Study found no relationship between consumption of corn, nuts or popcorn and the development of diverticulitis.41 An increased risk of acute diverticulitis has been reported from a Danish cohort of in-patient alcoholic patients who were followed up with record linkage from 1977 to 1993.42 The study reported a 2.0- and 2.9-fold increase in relative risk for men and women, respectively, following diagnosis of alcoholism. The authors speculated that the association could relate to the immunosuppressive effects of alcohol consumption. However, this association could also be due to an ascertainment bias due to increased investigation in alcoholics requiring hospital admission compared with the general population. A BMI of greater than 30 kg/m2 increased the relative risk of an episode of acute diverticulitis by 1.78 (95% CI, 1.08– 2.94) compared with a normal BMI in a cohort study of male American Health Care Professionals.43 Waist
circumference and waist-to-hip ratio were also independently associated with this. The mechanism responsible for this increased risk is unknown, but may include the pro-inflammatory nature of adipose tissue, which secretes cytokines that may promote the inflammatory response. Physical activity was reported to decrease the risk of developing diverticulitis in the same cohort by 25% (RR 0.75, 95% CI 0.58–0.95) when comparing those in the highest quintile of physical activity with those in the lowest.44 Smoking was reported to be associated with a threefold increased risk of diverticular complications including severe diverticulitis in a small retrospective study.45 A further study of patients from Finland reported an increased risk of recurrent episodes of acute diverticulitis in smokers following surgical intervention.46 Current users of aspirin and non-aspirin, nonsteroidal anti-inflammatory drugs are at a 1.25- and 1.7-fold increased risk of developing acute diverticulitis compared with non-users.47 It was postulated that this increased risk was due to mucosal damage resulting in impaired barrier function of the colonic mucosa allowing translocation of bacteria, which provoke inflammation.
Clinical presentation Patients typically present with left lower quadrant pain, although those with a large redundant sigmoid colon, may have suprapubic or right-sided pain if the sigmoid colon lies to that side. The patient may have diffuse abdominal pain indicating complicated disease such as perforation. The pain can be constant or intermittent and may be associated with nausea and vomiting in up to a third of patients.48 Change in bowel habit can occur with both constipation and diarrhoea, the latter being
Environmental influences Diet, microbiota
Genetic predisposition Weakening of Colonic wall
Neural degeneration Altered receptor sensitivity Circular/longitudinal muscle thickening
Elastosis
A g e i n g
Development of diverticulosis Faecolith impaction Micro perforation Environmental influences Diverticulitis Post inflammatory hypersensitivity 362
Chronic symptoms Pain, diarrhoea, constipation
Figure 1 | The possible pathogenesis of both diverticulosis and acute diverticulitis. Aliment Pharmacol Ther 2014; 39: 359-370 ª 2014 John Wiley & Sons Ltd
Review: diverticulitis pathogenesis and management more common in a recent review of presenting symptoms in patients to the emergency department with acute diverticulitis; however, the patient may rarely present with absolute constipation due to an underlying obstruction.35 The patient may report dysuria secondary to irritation of the bladder by the inflamed segment of colon. The differential diagnosis of acute colonic diverticulitis is listed in Table 1. On examination, the patient may be tender in the left lower quadrant with localised guarding and rigidity. Severe disease associated with peritonitis may present with a rigid board-like abdomen. Rarely, a mass may be palpable in the left iliac fossa. Bowel sounds may be depressed or increased in those patients with associated obstruction with a stricture. Rectal examination may be normal or elicit tenderness in the case of a pelvic abscess. Patients may have a fever and be tachycardic.
INVESTIGATIONS An algorithm for the investigation and management of patient with acute diverticulitis based on current clinical practice guidelines is shown in Figure 2. Bed side investigations should include a urine analysis to exclude urinary tract infection and pregnancy in women of child-bearing age, remembering that blood and protein in the urine may reflect bladder/ureter inflammation secondary to diverticulitis. Blood tests should include a full
Table 1 | The differential diagnosis of acute diverticulitis Gastrointestinal Acute diverticulitis Infective colitis Inflammatory bowel disease Ischaemic bowel Volvulus Malignancy Constipation Omental infarction Epiploic appendagitis Genitourinary Urinary tract infection Renal colic Prostatitis Gynaecological Ovarian cysts Ectopic Salpingitis Other Hernia Psoas abscess Retroperitoneal haemorrhage Aliment Pharmacol Ther 2014; 39: 359-370 ª 2014 John Wiley & Sons Ltd
blood count, urea and electrolytes along with a C-reactive protein and amylase or lipase (as local policy dictates). The clinical triad of left lower quadrant pain, fever and leucocytosis is often quoted in the diagnosis of acute diverticulitis; however, precise data on its accuracy are lacking. A recent retrospective study using HMO records in California found leukocytosis in 58.5% and temperature >37.5 °C in 30.1% of patients presenting to the emergency department with acute diverticulitis. However, the triad of abdominal pain, fever and leukocytosis was found in only 47% of those with severe findings on CT (abscess, perforation),35 indicating an unacceptable sensitivity, despite specificity of 95.2%. It is currently recommended that either CT or US scanning (depending on local expertise) should be undertaken within 72 h of admission to confirm the clinical diagnosis of acute diverticulitis and exclude any associated complications.49, 50 This position has been challenged and authors have attempted to identify severe cases that may benefit from imaging and reduce patient radiation exposure and health care costs in those with uncomplicated diverticulitis.48 The Longstreth study found severe CT findings in just 3.8%, of those with lower rather than generalised abdominal pain and no fever or leukocytosis, suggesting that for such patients, a wait and see approach might be cost effective without CT. The optimal imaging modality for patients with acute diverticulitis was recently the subject of a Cochrane review, which commented on how few high-quality studies there were.51 The review reported that ultrasound had a sensitivity of 84–99%, but a specificity of as low as 57% and as high as 100%, suggesting considerable local variability in expertise. Typical ultrasound appearances are of a thickened loop of bowel with a target-like appearance.52 The same review found a wide range of sensitivities for CT varying from 65% to 97% with a specificity of 77– 100%. The typical findings on CT are pericolonic fat stranding, bowel wall thickening and diverticular. Additional findings may include abscess, free fluid, free air, an inflamed diverticulum or the arrowhead sign in which contrast material shows an arrowhead configuration at the ostia of an inflamed diverticulum (Figure 3 shows an inflamed sigmoid diverticular segment with associated abscess).52 Studies comparing the two modalities are limited and the review concluded that it was difficult to draw firm conclusions, especially as the quality of CT has improved so much recently. The recent ACPGBI position statement concluded that the choice between the two modalities should be made on local expertise.49 The recent American College of Radiology Guidelines 363
D. J. Humes and R. C. Spiller
Bed side Urine dip Urine pregnancy test (child bearing age)
Presentation with suspected acute diverticulitis
Radiological Erect chest x-ray (if perforation suspected) Abdominal x-ray (if obstruction suspected) CT/US scan accoring to local expertise (all patients with a new diagnosis or those with suspected complications)
Admit Analgesia Commence treatment with broad spectrum antibiotics via local policy Discharge Analgesia Commence oral antibiotics via local policy
Follow up Colonoscopy at 8 weeks to exclude incidental cancer in new diagnosis No evidence of effective measures of prevention of recurrence
Laboratory Full blood Count Renal Function Creactive protein Amylase
Figure 2 | Investigation and treatment algorithm for patients presenting with suspected acute diverticulitis based on current guidelines.49, 50
suggested CT in the first instance as US was limited by operator expertise.52 Ultrasound, however, may have a role in premenopausal women and the young to reduce radiation exposure.53 Barium enema sensitivity varies from 29% to 93% with specificity of 50–100%, but its inability to visualise extra-luminal complications means that it is no longer used acutely.
Figure 3 | CT scan of acute sigmoid diverticulitis with associated abscess formation (white arrow), which required surgical resection. 364
RISK STRATIFICATION The majority (70–80%) of patients with acute diverticulitis can be managed without surgical intervention. There has been interest in predicting those patients who settle quickly on medical therapy and those that will require prolonged admission to attempt to reduce hospital stay and therefore health care burden. A retrospective review of 145 patients presenting to a University hospital identified reduction in leucocyte count and temperature over the 48 h from admission to be predictive of early discharge in patients with CT-confirmed acute diverticulitis receiving intravenous and then oral antibiotics.54 Along with limiting hospital stay, there have been attempts to better define those patients who may be treated at home. A study of out-patient management of 137 patients used ultrasound to confirm the diagnosis of acute diverticulitis and grade severity as mild to moderate. The study found that patients 2 cm could be successfully treated in the community with oral antibiotics and hydration with an out-patient review at day 4 and day 7. The success rate in such patients, who represented 55% of the total, was 97% (68/70) with an 80% reduction in treatment cost.55 A further study has evaluated the treatment of patients with uncomplicated diverticulitis in patients with comorbidity at home and found that after an 18-h hospital stay, 24 patients with comorbidity were successfully treated at home by a dedicated Hospital at Home team.56 A study of 693 patients who had acute diverticulitis Aliment Pharmacol Ther 2014; 39: 359-370 ª 2014 John Wiley & Sons Ltd
Review: diverticulitis pathogenesis and management confirmed on CT and were subsequently discharged home from the emergency room found only a 6% treatment failure rate defined as return to the emergency room or admission with acute diverticulitis within 60 days.57 Female patients and those with free fluid on CT were at greatest risk of treatment failure. A further study of 132 patients with CT proven uncomplicated acute diverticulitis randomised treatment in the community or hospital admission demonstrated no difference in failure rates of treatment between the two groups, but found lower costs in the community treated group.58 The use of mesalazine in patients with uncomplicated symptomatic diverticular disease has been proposed with a recent randomised trial reporting a nonsignificant reduction in median lower abdominal pain in the mesalazine group.59 Reliable identification of patients with acute diverticulitis who may be safely treated in the community is required and further research is needed in this area to maximise the potential benefits of avoiding hospital admission for patients and to reduce health care costs.
TREATMENT Conservative/Medical There has been increased interest in treating patients with acute diverticulitis conservatively. Addressing known risk factors such as obesity, lack of physical activity, alcohol and smoking in theory might reduce the risk of developing acute diverticulitis in an individual within known diverticulosis or reduce recurrent attacks,
although there is as yet no direct evidence to support this idea.60 Over recent years, there has been a challenge to the traditional treatment of acute diverticulitis with antibiotics and admission to hospital. Conservative treatment of acute diverticulitis normally includes bowel rest with intravenous fluids and antibiotics with appropriate analgesia. Until recently, there was a lack of randomised controlled trials that compared antibiotic treatment with no antibiotic treatment. Trials had largely focused on comparison of different antibiotic regimes.61, 62 An initial publication of a retrospective review of 311 patients admitted to a single Hospital in Sweden demonstrated that managing mild acute diverticulitis without antibiotics, but merely bowel rest and observation lead to no increase in adverse events compared with those patients treated with antibiotics who were generally sicker with more severe CT grading.37 These findings encouraged a randomised controlled trial of antibiotics in patients with acute uncomplicated acute diverticulitis from Sweden, which reported no difference in complications such as abscess or perforation between those treated with or without antibiotics with a median length of stay in both groups of 3 days.63 This study, however, was criticised for excluding patients with sepsis (though no definition of sepsis was provided) and for problems with possible selection bias, given that not all patients eligible for the study were recorded. It remains to be seen if these results are generalisable. Table 2 summarises the trials to date detailing the role of antibiotics in the treatment of patients with acute diverticulitis. Given the rise in noso-
Table 2 | Summary of randomised trials of antibiotic treatment in patients with acute diverticulitis Author Kellum et al.
Trial Patients design (n) Diagnosis RCT
51
Ridgway RCT et al.
80
Chabok et al.
623
RCT
Duration
Endpoint
Significance
Clinical cure NS Clinical diagnosis of 30 intravenous cefoxitin (1–2 g every acute diverticulitis 6 h) 21 intravenous gentamicin (1.7 mg/kg loading dose then 1.0–1.4 mg/kg every 8 h) plus clindamycin (2400–27 000 mg/day in three or four divided doses) NS Clinical diagnosis of 41 oral ciprofloxacin (500 mg b.d.) and Abdominal tenderness acute diverticulitis metronidazole (400 mg t.d.s.) vs. 38 at day 3 IV ciprofloxacin (400 mg b.d.) and metronidazole (500 mg t.d.s.) Development of NS CT verified 309 no antibiotics vs. 314 antibiotics a complication uncomplicated (given according to local policy (perforation/abscess) acute diverticulitis second or third generation cephlasporin and metronidazole or carbopenam or piperacillin
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D. J. Humes and R. C. Spiller comial infections particularly Clostridium difficile associated colitis and antibiotic resistance, it would seem desirable to be able to restrict the use of antibiotics in this large patient group to only those that may benefit. Further trials in this area are required and we await the result of the DIABOLO trial,64 which is a randomised trial of 48 h of intravenous antibiotics, admission to hospital and bowel rest vs. a liberal strategy of no antibiotics and admission if only clinically indicated for radiologically proven, uncomplicated, acute diverticulitis. The primary endpoint of the study is full recovery within 6 months. It is hoped that this will clarify the management of this group of patients with radiologically proven acute diverticulitis. There has been growing interest in the role of antibiotics, 5-aminosalicylates and probiotics in the prevention of recurrent attacks of acute diverticulitis. Studies to date have generally been of poor methodological quality and so deriving clear guidance from these is difficult. Several systematic reviews have concluded that the evidence for these interventions is weak and further high-quality randomised controlled trials are required to prove efficacy.65–67 The most recently published RCT in this area compared mesalazine, or mesalazine plus Bifidobacterium infantis 35624 for 12 weeks and followed up for nine additional months. Global symptom scores were assessed over the 52 weeks of follow-up.68 No statistical difference in symptom scores was found; however, those receiving mesalazine did have a consistent trend in reducing symptoms. The addition of a probiotic failed to increase the efficacy of mesalazine. Recent studies suggesting that mesalazine may be beneficial in IBS69 complicate interpretation of diverticular studies as it may be hard to distinguish uncomplicated diverticular disease from IBS and this may explain some of the benefit reported with mesalazine in previous studies. More recently, a large well-designed RCT examined the effect of 48 weeks of mesalazine 3 g daily vs. placebo in patients with a recent (
