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Highlights from Gastro Update Europe – Prague, April 29–30, 2016
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Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Congress Report
Highlights from Gastro Update Europe – Prague, April 29–30, 2016
These highlights summarise a selection of the most important gastrointestinal discoveries of high clinical relevance presented at the recent Gastro Update Europe in Prague. The selected topics are indicative of what the faculty considered to be essential to be communicated to the astute busy gastroenterologist in clinical practice, who wants to stay abreast of clinically important developments. Whenever appropriate a personal note or comment is included to further raise the educational level of these highlights. Gastro Update Europe, a truly intense educational enterprise, presented and discussed by top opinion leaders in gastroenterology and hepatology, is a unique teaching format of yearly rising scientific quality. Disorders of the proximal digestive tract Peter Malfertheiner Lecture – Gastro Update Europe 2016 – Prague. Prof. Peter Malfertheiner from Germany reviewed the most salient recent achievements in the upper intestinal tract. Gastrooesophageal reflux disease (GERD) continues to be one of the leading diagnoses in ambulatory care both in the USA and in Europe. Proton pump inhibitors (PPI) remain by far the first drug class for the initial therapy for symptomatic GERD, with a trend to increase the dose and the frequency of dosing. Even stronger inhibition of acid secretion is possible with a so-called potassium competitive acid blocker (p-cab) such as vonoprazan. Vonoprazan binds immediately and selectively to both active and resting pumps in the parietal cell; the slow dissociation from the pump explains the long-lasting acid inhibition. Moreover, the drug is not influenced by Cyp2C19 genotype. Vonoprazan shows impressive prolonged acid secretory inhibition, so far with few if any adverse effects (in contrast to previous p-cab attempts). It is to be expected that the spectacular Japanese results will be confirmed in the West and that the drug ultimately will become available in Europe. What the proper indications and mode of administration of this superior acid suppressant will be in clinical practice will require detailed study in view of the non-negligible consequences of prolonged profound acid suppression. The use of PPIs, even very long-term, is generally considered as rather safe. Yet clinicians should remain vigilant for possible adverse effects (magnesium, vitamin B12 etc). Earlier studies pointed to a potentially enhanced risk of PPIrelated community-acquired respiratory tract infection, but in a recent retrospective analysis of over 14,000 patients, there was no causal association between esomeprazole versus placebo in
the occurrence of community-acquired respiratory tract infection and pneumonia, which is certainly reassuring. The PPI-clopidogrel controversy is fading away; indeed an updated meta-analysis was presented regarding the incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without PPIs. The myocardial infarction rate and the overall mortality were indistinguishable between the 2 groups, which again is reassuring. More annoying is perhaps the relationship between PPI use and chronic kidney disease. In a study of the risk for atherosclerosis in 10.000 community participants, PPI use (which was more common in Caucasians, the obese and users of antihypertensives) was associated with chronic kidney disease, especially with twice-daily dosing. This finding contrasts with the detailed analysis of the long-term comparison of anti-reflux surgery versus prolonged PPI therapy where essentially no laboratory abnormalities were discovered between the 2 groups. One can only speculate why some participants in the atherosclerosis study were at risk for chronic kidney disease (pre-existent latent kidney disease, pharmacological interactions, confounders, etc). Anyhow, significant laboratory anomalies are not to be expected in reflux patients on PPI monotherapy. Intriguing was a recent pharmacoepidemiologic study showing an increased risk of dementia in PPI users. Obviously a prospective randomised clinical trial is mandatory to establish a direct cause and effect relationship between PPI use and incident dementia in the elderly. Such a study will be extremely difficult to carry out, but of high clinical relevance in view of the rising dementia and PPI use in the elderly, often as a gastric mucosal protectant. Several studies analysed the (major) effects of long-term PPI use on the colonic microbiota, and especially on the rising risk of Clostridium difficile infection. There is a significantly lower abundance in gut commensals, and a lower microbial diversity in PPI users, with a significant increase in oral and upper gastrointestinal tract commensals together with increased numbers of enterococ, streptococ, staphylococ and potentially pathogenic Escherichia coli. The observed changes may well result from the removal of the low pH gastric barrier (the so-called acid steriliser). Alginate/antacids such as Gaviscon double action, active particularly in the area of the acid pocket in the upper stomach are usually used as add-on therapy for insufficiently controlled or break-through symptoms during PPI therapy for reflux control. A recent large Chinese study showed that Gaviscon (2 tablets 4 daily) as monotherapy could successfully relieve symptoms in mild to moderate GERD. It seems somewhat doubtful whether
http://dx.doi.org/10.1016/j.ajg.2016.08.002 1687-1979/Ó 2016 Published by Elsevier B.V. on behalf of Pan-Arab Association of Gastroenterology.
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such results could be confirmed in the west and whether it would change the PPI dominance as first-line therapy for GERD. Eesophageal columnar metaplasia or Barrett oesophagus, present in 1–2% of the general population and some 10% of GERD patients, continues to generate major attention largely because of the 30–40% increased risk of oesophageal adenocarcinoma. Remember that the majority of Barrett patients will not progress to cancer and that only some 5% of adenocarcinoma patients have been identified as Barrett carriers before cancer diagnosis. Is it possible to reduce the cancer risk? The overall risk of neoplastic progression can be reduced by some 30% with aspirin/NSAID therapy, by some 48% with statin therapy and by some 67% with PPI. Based on these data, many clinicians prescribe prolonged PPI therapy also in asymptomatic carriers of columnar metaplasia. Solid information upon which to base guidelines for endoscopic/bioptic surveillance (a hotly debated topic) does not exist. There is some consensus that surveillance of non-dysplastic Barrett, to decrease the risk of cancer death, should only be considered and targeted to high-risk groups: age >50 y, Caucasian, male gender, the obese, symptomatic. Also, the length of the Barrett segment is relevant. Of over 1.000 T1 adenocarcinomas, 56% occurred in long segment (>3 cm) Barrett oesophagus. The estimated annual cancer transition in long segment was 0.22%. Few would now disagree that patients with high-grade dysplasia should be amenable to preferentially endoscopic therapy (resection with radiofrequency ablation). A new American trial confirmed that patients with well established low-grade dysplasia should also be amenable to radiofrequency ablation. The annual rates of progression to high-grade dysplasia/early adenocarcinoma in that study were 6.6% in the surveillance arm compared to 0.77% in the radiofrequency arm. Eosinophilic oesophagitis remains the most intriguing novel oesophageal disorder. The rising frequency, at least in the West, is genuine. A large Danish study showed that the increased incidence and prevalence outpaces the changes in endoscopy and biopsy practice. The rise of the disease remains largely enigmatic. Insufficient microbial/parasitic allergen exposure early in life may well contribute to a predominance of a Th2- type immune response pattern later in life. A simplified pathophysiologic scheme is shown below.
D’Alessandro A et al. Pathological mechanisms underlying therapy of EoE. World J Gastrointest Pathophysiol 2015;6:150
In the traditional definition, eosinophilic oesophagitis does not respond to acid suppression. Yet many patients with eosinophilic inflammation do seem to respond to PPI therapy, the so-called PPI-responsive oesophageal eosinophilia, leading to the concept that PPI-REE was a separate entity. However, sufficient data have
been presented to show that eosinophilic oesophagitis and PPIREE are almost indistinguishable also from a genetic point of view. It would appear that in the initial and mild phases of the disease, symptoms may respond to acid inhibition. PPIs have anti-inflammatory effects, but PPI-responsiveness may gradually disappear as the fibrotic remodelling of the disease progresses. Therefore the first therapeutic approach is PPI therapy. Should PPI therapy fail, topically active corticosteroids should be tried. In a large multicentre trial budesonide effervescent tablets (twice 1 or 2 mg) or viscous suspension (twice 2 mg) were compared versus placebo, and both showed high histological remission rates. Gastrointestinal bleeding remains a major life-threatening emergency, especially in the elderly and is of major current interest in view of the rising use of the novel non-vitamin K antagonist anticoagulants (noacs). In a large population-based cohort study, the hazard ratio of gastrointestinal bleeding with dabigatran was 2.29, with rivaroxaban 2.84, and with warfarin 2.87. In patients with atrial fibrillation, the risk of bleeding with dabigatran was less compared with warfarin, except for patients older than 75 y. This was confirmed in a meta-analysis of 23 studies comparing the risk of major gastrointestinal bleeding with non-vitamin K oral anticoagulants (noac) versus warfarin, showing that the bleeding risk in atrial fibrillation was not different between noacs and vitamin K antagonists. Fortunately the risk of dabigatran-related gastrointestinal bleeding can be reduced by gastroprotective agents as shown in a population-based study where the bleeding risk was 2.5% and was lowered to about half with gastroprotective agents. Detailed analysis of 10 randomised controlled trials regarding the use of PPI in the prevention of low-dose aspirin-associated upper gastrointestinal injury led to the following conclusions: PPIs decrease the risk of low-dose aspirin-associated upper gastrointestinal ulcers with 84% and of bleeding with 73%; for patients treated with dual anti-platelet therapy of low-dose aspirin and clopidogrel, PPIs prevent bleeding in 64% without increasing the risk of major adverse cardiovascular events. Moreover, PPIs were markedly superior to H2RAs in ulcer and bleeding prevention. Protection was also shown in a nation-wide Scandinavian study which showed that the use of PPI was associated with a decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with NSAIDS. The overall age-standardised incidence of gastric cancer (8.8 per 100,000) and cardiac cancer (3.3 per 100,000) remains high with 5-y survival rates of less than 25%. Helicobacter pylori infection, especially with virulent strains, remains the leading cause through pre-neoplastic remodelling of the gastric mucosa. Ideally, H. pylori should be eradicated before the development of irreversible pre-neoplastic lesions. The risk of cancer increases from gastritis, atrophic gastritis, intestinal metaplasia and dysplasia. The Olga system is increasingly used to monitor the changes in the gastric mucosa and to estimate the cancer risk. Arguments have been presented to take an additional biopsy of the angulus next to the standard antrum and corpus biopsies as this raises the detection of atrophy and intestinal metaplasia. Since the quality of the endoscopic equipment is continuously improving, there is a trend to move away from non-targeted to targeted biopsies, directed to areas of minor abnormality, only detectable with high-definition endoscopes, with or without supplementary technologies (chromo, NBI etc). The demand for high-quality equipment such as high-definition is supported by a sobering British retrospective analysis, revealing that 8.3% of patients with gastric cancer had their malignancy missed at endoscopy carried out within the 3 previous years. Screening of high-risk individuals and subjects in high-risk areas should ideally be conducted with the so-called gastropanel (measuring gastrin17, pepsinogen I, II, and ratio, and anti-H. pylori antibodies). As already stated, ideally H. pylori eradication should
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occur before gastric mucosal neoplastic remodelling, but even after endoscopic resection of gastric neoplasia, eradication may be indicated to prevent metachronous lesions in approximately 60%, as shown in a recent meta-analysis. There is a manifest revival of bismuth-based therapy for H. pylori eradication. The Maastricht V-2016 edition recommends for areas with high (>15%) clarithromycin resistance, bismuth quadruple or non-bismuth quadruple therapy (PPI, amoxicilline, clarithromycin, nitroimidazol). In areas of high dual clarithromycin and metronidazole resistance, bismuth quadruple therapy is the recommended first line treatment. Apparently concomitant nonbismuth quadruple therapy is superior to sequential therapy. Bismuth appears to act, not by direct interaction with urease or the urea channel in the inner bacterial membrane, but by impeding proton entry in the organism. The diminished fall in cytoplasmic pH with acidification in the surrounding medium favours upregulation of the genes involved in growth, which allows augmented efficacy of the growth-dependent antimicrobials. Amoxicillin can be used instead of tetracycline in first-line bismuth quadruple therapy as shown in a large important Chinese study comparing 14 d therapy with bismuth, lansoprazole, amoxicillin, and metronidazole (cure rates 94 and 93% for metronidazole sensitive versus resistant) and bismuth, lansoprazole, amoxicillin, and clarithromycin (cure rates 99 and 77% for clarithromycin sensitive versus resistant). Overall recommendations in case of eradication failure are summarised below:
1st line
2nd line
3rd line
Regions with low ClariR prevalence
Regions with high ClariR prevalence
PPI-Clari-Amoxicillin/metronidazole or Bismuth Quadruple
Bismuth Quadruple
Bismuth Quadruple or PPI-Levofloxacin/Amoxicillin
if not available Non-Bismuth quadruple
PPI-Levofloxacin/Amoxicillin
Based on susceptibility testing only Malfertheiner et al., GUT 2012 May;61 (5):646-64 ; GUT 2016 subm
Novel eradication schemes have been attempted in case of eradication failure with non-bismuth quadruple therapy such as:
– bismuth, esomeprazole, amoxicillin, levofloxacin (cure rate 74% in highly resistant patients: amoxicillin 8%; clarithromycin 56%; metronidazole 74%; levofloxacin 36%); – bismuth quadruple; omeprazole and pylora (=bismuth subcitrate, tetracycline, metronidazole) for 10 d (cure 83% in patients with resistance to metronidazole, clarithromycin and fluoroquinolone or with multiple prior treatment failures); – adding rifabutin to pantoprazole and amoxicillin or rifabutin to pantoprazole, amoxicillin, and bismuth. More intensified acid suppression with the novel p-cab vonoprazan was shown to improve the eradication rates from 76% [lansoprazole, amoxicillin, clarithromycin] to 93% [vonoprazan,
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amoxicillin, clarithromycin] in over 600 gastroduodenal ulcer patients. Novel developments in pancreatic disorders Peter Layer Lecture – Gastro Update Europe 2016 – Prague. Prof Peter layer from Germany analysed the recent novel findings with respect to pancreatic diseases. First discussed was acute pancreatitis, still a devastating entity. Excessive alcohol intake and smoking are well established causes of chronic pancreatitis; their role in the pathogenesis of acute pancreatitis is less clear. A large case-control study compared over 500 patients with acute pancreatitis to over 10,000 matched controls. It was clearly shown that the risk of acute pancreatitis rises with rising daily alcohol intake: 50 g-3-fold; 70 g-4.2fold; 90 g-5.3fold; >100 g-6.4-fold. Also, tobacco smoking increases the risk of acute pancreatitis approximately 2-fold, as shown in a meta-analysis of 12 studies. Clinicians should therefore be aware that smoking is a potential cause of ‘idiopathic’, especially relapsing acute pancreatitis. Such patients should therefore be strongly advised to quit smoking. How smoking leads to acute pancreatitis remains poorly understood. What is also insufficiently realised in practice is that pancreatic cancer may occasionally present as acute pancreatitis. In a large American cohort with over 500,000 subjects, approximately 1 in 10 pancreatic cancers manifested first as acute pancreatitis. Most cancers became overt within 2 y post the presentation with acute pancreatitis. Whenever therefore, the cause of acute pancreatitis is not clear, meticulous EUS examination of the pancreas is indicated in order not to delay the detection of the underlying malignancy. Hypertriglyceridaemia is a well established cause of acute pancreatitis. Disease severity and risk of persistent organ failure are high, and parallel the severity of hypertriglyceridaemia: mild <200; moderate <1000; severe >1000 mg/dl. It is beyond doubt that hypertriglyceridaemia is strongly associated with severe and complicated acute pancreatitis, either as the sole aetiology or as amplifier of other causes. The involved pathogenetic mechanisms and therapeutic possibilities are insufficiently elucidated. Most intriguing is the potential preventive role of statins in the prevention of acute pancreatitis, as analysed retrospectively in 4 million Californian subjects: acute pancreatitis risk (of any cause) was some 70% reduced in statin (simvastatin) users, especially with a dose of >10 mg/d. As many confounders may be involved, these data beg for a prospective randomised study. How statins may be potentially preventive also needs further study. Up to now, there has been little consensus with respect to the timing of cholecystectomy after (mild) biliairy pancreatitis. In an important study, over 250 patients with mild biliairy pancreatitis [CRP < 100 mg/l; opiate-free pain control; oral refeeding] were randomised to immediate surgery (within 3 d of admission) versus delayed surgery (>25 d after discharge). There was a 70% decrease in relapse of biliairy symptoms and pancreatitis or death within 6 months in the Group with immediate surgery during the index hospital admission. These results are quite persuasive and deserve to be followed-up in practice. Whether and when antimicrobials should be used in acute necrotising pancreatitis remains a moot and controversial point. An earlier meta-analysis showed a 40% reduced mortality with antimicrobial therapy (betalactam, imipenem) but all studies had considerable methodological flaws and deficits. In a novel metaanalysis of 6 randomised controlled trials involving close to 400 patients with acute necrotising pancreatitis, early antimicrobial administration led to a 50% reduction in overall mortality and 45% reduction in infected necrosis. Early antimicrobial therapy
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is probably useful in individual patients with extensive necrosis or a predicted severe disease course. Previous studies have shown that oral refeeding may start early in mild, and even more severe pancreatitis, but refeeding attempts are not always successful, especially in patients with hypertriglyceridaemia or with persistently elevated enzymes (lipase >2 times the norm). It is preferred not to force oral feeding from day one but to use recurrence of appetite as a reliable indicator for successful oral refeeding. Healing of severe acute pancreatitis may be associated with morphological and functional defects. A meta-analysis of 8 follow-up studies involving 234 patients with acute pancreatitis, revealed that 43% developed diabetes mellitus, 29% pancreatic exocrine insufficiency and 40% both sequellae. Appropriate follow-up is therefore mandatory. Alcohol consumption is a well-known and established cause of chronic pancreatitis. A recent high-quality case-control study involving over 400 patients and over 1000 matched controls revealed an impressive alcohol dose–response risk; for daily alcohol intake of 30, 50, 70, 90, and >100 g, the risk for chronic pancreatitis rose from 2.8, 3.2, 9.2, 13 and 19.5 times respectively. In simple terms: daily alcohol consumption <20 g: no risk; moderate risk with linear increase at 20–60 g/d; rapid increase in risk beyond 60 g/d (>2 glasses of wine; >pints of beer). Correlation between symptom pattern and severity and morphological objective alterations is often poor in gastroenterology. The same holds for chronic pancreatitis where no correlation between pancreatic morphological changes (obstruction, inflammation, pseudocysts etc.) and symptom pattern or severity is apparent. Interest in autoimmune pancreatitis remains intense. As a reminder, there are apparently 2 types: the more frequent type 1 (IgG4-associated systemic disease, often involving multiple organs) and type 2 (isolated pancreatic disease, concomitant IBD). Type 2 has been further characterised in 43 patients: 58% presented initially as relapsing acute pancreatitis; 36% presented initially as mass lesion and obstructive jaundice (mimicking cancer); 50% had associated IBD and 11% relapsed within 3 y after treatment. Early diagnosis is essential as the prognosis is excellent with adequate (corticosteroid) therapy. There is consensus that in principle, main duct intraductal papillary mucinous neoplasm (IPMN) should be treated surgically as cancer will develop in 1 out of 3 patients within 3 y. For branch duct IPMN, surgery is indicated for lesions larger than 3 cm, diameter of the pancreatic duct >5 mm, presence of intramural nodules and suspicious cytology. A large study evaluated the survival in patients with main duct IPMN that could not be resected for various reasons: 5 y survival in the resected group was 74% versus 58% in the non-resected group; those older than 70 y had a significantly worse outcome as expected (comorbidities, reduced operability etc). Statin use was also evaluated in the survival of over 200 patients resected for early-stage pancreatic cancer. Simvastatin reduced the mortality by 44% and the relapse rate by 39% if a high dose was used. It is utterly intriguing why simvastatin may improve the prognosis following curative resection of early-stage pancreatic cancer. Prospective, high-quality studies are urgently needed to consider simvastatin use as standard adjunctive anticancer therapy.
Developments in digestive endoscopy Andrea May, Marco Bruno and Bjorn Rembacken Lectures – Gastro Update Europe 2016 – Prague. Prof Andrea May from Germany covered endoscopic achievements in the upper gastrointestinal tract.
There is no global consensus on the need and the characteristics of surveillance of patients with oesophageal columnar metaplasia (Barrett). Most would agree that surveillance is only clinically indicated when the neoplastic risk is truly enhanced. Based on a large cohort of over 1000 oesophageal early adenocarcinoma, cancer was more common in long segment Barrett (>3 cm) (56%) compared to short segment (<3 cm) metaplasia (24%). The authors conclude that the cancer incidence per 100,000 population is 3.3 for long segment compared 1.4 for short segment. Based on these findings, it would appear that Barrett length should be integrated in the surveillance advice: every 2–3 y for long segment, every 5 y for short segment. We are again reminded that surveillance is a difficult procedure, requiring optimal equipment, optimal dedication, and expertise for adequate detection of neoplasia. In a prospective surveillance study of routine clinical practice of 121 patients with Barrett neoplasia, only one third of the neoplastic lesions were correctly identified at endoscopy. The other two thirds were initially considered as non-suspicious aberrations; particularly type IIb (flat, non-elevated) were prone to misinterpretation. Because detection and proper identification of flat neoplasia is difficult, it is probably still wise to take 4-quadrant non-targeted biopsies during the index endoscopy to diminish the risk of missing neoplastic changes. Peroral endoscopic myotomy (POEM) was added to pneumodilation and laparoscopic Heller myotomy for the treatment of achalasia. The long-term results of the large multicentre prospective trial comparing pneumodilation to laparoscopic myotomy have become available. In that study, re-pneumodilation was allowed twice if this therapy was initially successful and if symptoms recurred beyond 2 y after the first pneumodilation; treatment failure was decided if symptoms recurred sooner. Respective per protocol 5 y success was 91 versus 82%, and intention-to-treat success was 82 versus 84% for pneumodilation and laparoscopic myotomy; perforation occurred in 5% after pneumodilation and mucosal injury occurred in 12% after myotomy. This study therefore illustrates that both techniques are comparable from a clinical point of view. The choice of therapy should at large be based on local expertise. Certainly in the younger patients (<40 y) myotomy by an experienced surgeon deserves to be considered. Whilst the technique of POEM continues to improve, follow-up data from the initial studies are becoming available. 80 patients from a multicentre study were followed-up for 2–3 y. The initial success rate of 96% dropped to 78% beyond 2 y of follow-up. Initial failure (4%) and disease recurrence (18%) occurred mainly during the learning phase of the procedure. Endoscopic reflux oesophagitis was diagnosed in 40% (!) of the patients, usually requiring prolonged PPI therapy. POEM is certainly an attractive novel procedure but may not be superior to the other treatment modalities, and cannot yet be recommended as the new standard therapy of choice. Endoscopic haemostasis with haemostatic powder (such as haemospray etc) continues to be explored particularly with respect to the proper indications (diffuse bleeding, difficult bleeding areas to reach, failure of other haemostatic modalities, etc. In a study with 40 patients with upper-intestinal, non-variceal bleeding, initial haemostasis was obtained with haemospray in 95% but bleeding recurred in 30%. Interestingly, no haemostatic powder was endoscopically detectable after 24 h. For the time being, haemostatic powder should be considered as a reserve method together with the standard endoscopic haemostatic modalities: injection of saline/epinephrine; mechanical clipping and ligation; thermal electrocoagulation. The number of patients on anticoagulants (vitamin-K antagonists, such as warfarin or the novel oral anticoagulants, such as dabigatran) that need an endoscopic procedure is increasing. Low risk procedures are upper and lower endoscopy + biopsy, biliary
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or pancreatic stenting, and diagnostic EUS. High risk procedures include: polypectomy, sphincterotomy, EUS with fine needle aspiration, PEG, variceal banding and stricture dilation. To prevent peri-operative bleeding, inpatients with atrial fibrillation, warfarin is usually stopped 5 d before the procedure and low-molecular weight heparin is given as peri-operative bridging. Warfarin can be resumed within 24 h after the procedure. In a large study with almost 2000 patients with atrial fibrillation, heparin was compared with placebo as bridging in patients with a mean CHAD2 score of 2, 3; arterial thromboembolism occurred in 0.3 versus 0.4% but major bleeding in 3.2 versus 1.3% respectively in the heparin versus the placebo group. The authors conclude that for low risk interventions and a CHAD2 score 62, no bridging with heparin is required and warfarin can be resumed within 2 h after the procedure at the usual dose. Currently, the CHA2DS2-VASc scoring system is often used. Following points are given: congestive heart failure 1, hypertension 1, age P75 y 2, diabetes 1, stroke 2, vascular disease 1, age 65–74 1, female gender 1. Interest in full (transmural) thickness resection of localised mural lesions throughout the gastrointestinal tract is rising, and dedicated full thickness resection devices have recently been described. Obviously such technology should be in the hand of highly experienced endoscopists, in a centre with full expertise in endoscopic emergencies, but the expectation is that such endoscopic approaches will expand. The wall defect is usually closed before transmural transection, with a large over-the-scope (OTC) clip. An alternative is to suture the defect with a suturing device (over-stich; plicator; Gerdx etc). Balloon-assisted endoscopy is increasingly performed in patients with Crohn disease. In a retrospective analysis of almost 30,000 patients examined with balloon-assisted endoscopy, the overall perforation rate was 0.1%, but the risk increased 2.5-fold in Crohn, 3-fold in steroid users and 9-fold in the latter combination. Utmost attention is therefore mandatory in the presence of ulcerated lesions and concomitant steroid therapy. A rising alternative to endoscopy is dedicated MRI enterography for primary diagnosis but also for monitoring therapy. There is even some hope that in the future, MRI-based differentiation between inflammation and fibrosis will be possible and quantifiable, which will have major impact in the choice of therapy. Prof Marco Bruno from the Netherlands covered the recent findings of clinical relevance in the biliopancreatic area with ERCP and EUS. First discussed was the role of endoscopic sphincterotomy for suspected sphincter of Oddi dysfunction, which is commonly performed in the USA. In a landmark multicentre American sham-controlled randomised trial involving over 200 patients with pain after cholecystectomy, without significant abnormalities on imaging or laboratory studies and without prior sphincter treatment or pancreatitis, sphincterotomy was compared to sham therapy with follow-up blinded lasted for 1 y. After ERCP patients were randomised irrespective of sphincter manometry findings. Those randomised to sphincterotomy with elevated pancreatic sphincter pressure were randomised again to biliary or to both biliary and pancreatic sphincterotimy. The outcome was essentially negative; sphincterotomy (either biliary or combined biliary and pancreatic) was no better than sham placebo in relieving symptoms. Physicians should therefore be utterly reluctant to carry out a (risky) sphincterotomy if in the absence of imaging or lab abnormalities. Already in a somewhat older study, it was shown that rectal NSAIDs reduce the incidence of post-ERCP pancreatitis, which occurred in 9% of the indomethacin group, compared to 17% in the placebo group. Based on such findings, it is usually recommended to administer rectally 100 mg indomethacin or diclofenac before or after ERCP, especially in patients with an elevated baseline risk [suspected sphincter of Oddi dysfunction; prior pancreatitis; precut sphincterotomy; >8 cannulation attempts; sphincter dilation; ampullec-
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tomy] or in patients with 2 or more minor criteria [age >50 y; female gender; prior recurrent pancreatitis; >3 contrast injections in the pancreatic duct; high pressure acinarisation; duct cytologic sampling]. Perhaps these recommendations for rectal NSAIDs may not be as straight forward as initially thought because of the findings in a large general practice study (with 70% at average post-ERCP pancreatitis risk) comparing 100 mg rectal indomethacin versus placebo suppository. The study did not show protection against pancreatitis, defined by new upper abdominal pain, lipase >3-fold the upper normal level, and need for hospitalisation. Putting all information together (including some recent positive studies), it is probably wise to still continue to use rectal NSAIDs in clinical practice. By the way, parenteral administration of NSAIDs has not been shown to be effective as pancreatitic prophylaxis in the past for unknown reasons. It is widely accepted that palliative drainage of malignant common bile duct obstruction should be first attempted endoscopically. Initial insertion of a 10 Fr plastic stent is recommended if the diagnosis of malignancy is not established or if expected survival is <4 m. No drug prescription is recommended to prolong stent patency. In patients with an established diagnosis of malignancy, initial insertion of a 10 mm diameter self expanding metal stent is recommended if expected survival is >4 m or whenever the cost of such a stent is less than half the ERCP cost. A recent study with over 200 patients compared stent patency for plastic stents (172 d), uncovered (288 d) and partially covered selfexpanding metal stents (299 d). Total costs per patient at the end of the follow-up period did not differ between plastic stents and metal stents. Even in patients with <3 m survival or metastatic disease, costs did not differ. Thus in the palliation of extrahepatic biliary obstruction, self expanding metal stents have a longer functional time and total costs do not differ significantly with stent type. The standard endoscopic therapy for choledocholithiasis is endoscopic sphincterotomy and basket or balloon facilitated stone extraction. Complementary techniques for removal of large or multiple stones are mechanical lithotripsie, electrohydraulic lithotripsy, cholangioscopy with (Holmium) laser lithotripsy or extracorporeal shockwave lithotripsy. To find out if it is possible to extract large (>15 mm) or multiple (>3) stones after widening the sphincterotomy opening with a large balloon, a comparative study was performed in 70 patients comparing spincterotomy with or without balloon dilation. Complete stone removal was achieved overall in respectively 100 versus 89%; in the first session in 88 versus 56%; pancreatitis occurred in 6 versus 23%; haemorrhage in 3 versus 6%; there were no perforations. Papillary large balloon dilation, with or without endoscopic sphincterotomy was retrospectively analysed in 2 other studies and revealed similar rates of large/multiple stone removal (100 versus 98%) and adverse event rates (4 versus 7%). Based on these data, American guidelines state that papillary large-balloon dilation can be used as the initial method when large common bile duct stones have been identified. If retrograde cannulation of the biliary tree fails in case of distal malignant obstruction, percutaneous transhepatic cholangiography is often attempted. The latter technique may lead to complications (bleeding, bile leak, sepsis, peritonitis) and may cause mortality (0.6–5.6%). Novel is the possibility of EUS guided transmural drainage, preferably using an all-in-one device for puncture and deployment of a partially covered metal stent or increasingly, a lumen-apposing (diabolo-type) stent. A multicentre Korean study compared EUS-guided internal versus percutaneous drainage for unresectable malignant distal biliary obstruction and inaccessible papilla. Respective technical success was 94 versus 97%, functional success was 88 versus 87%, adverse events 9 versus 31%, reintervention rate 25 versus 55%. Stent patency and overall survival were comparable. It would appear that EUS-guided internal biliary
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drainage may well become the therapy of choice in the future now that stent design and equipment continues to improve. Conflicting data have been reported regarding the clinical impact of on-site cytopathology evaluation during EUS-guided fine needle aspiration of pancreatic masses. Observational studies have suggested that the absence of on-site cytopathology is associated with a 10–15% reduction in definite diagnosis and number of adequate specimens. Because a randomised controlled trial, comparing the impact of on-site cytopathology on the diagnostic yield and overall accuracy is lacking, a large American trial was conducted involving 240 patients. Respectively with versus without on-site cytopathology revealed a median number of needle passes of 4 versus 7, inadequate specimens of 10 versus 13% and overall accuracy of 88 versus 89%. It would therefore appear that in high volume centres there is no difference in the diagnostic yield of malignancy, accuracy, procedure time and costs between patients with pancreatic masses undergoing EUS-fine needle aspiration with or without on-site cytopathology. An obvious alternative to all this would be that the endoscopist of the future obtains some basic training in cytology slide production and evaluation, but whether this is realistic remains to be seen. Prof Bjorn Rembacken (UK) analysed endoscopy in the lower gastrointestinal tract. He first discussed the important issue of bowel cleansing. Most difficult to clean are the elderly, cirrhotics, constipated and obese patients. Adding lubiprostone to the polyethylene glycol (PEG) solution does not help. A split-dose regimen gives overall better results than the day-before cleansing, but same day cleansing is even better than splitting over 2 d. The better the cleansing result, the more sessile serrated lesions and advanced adenomas are detected, and the lesser flat lesions are missed. The higher the experience, the higher the caecal intubation rate (usually somewhat lower in women and the elderly). Cap-assisted colonoscopy has been shown to improve the adenoma/polyp detection rate, especially in the right colon. Prolonging the withdrawal/observation time beyond 6 months increases the polyp detection rate but also decreases the risk of interval cancer occurring after the colonoscopy. Using a spasmolytic (often mebeverine) during the procedure may marginally improve the procedure. Endoscopic retroversion, not only in the rectum but also in the right colon enhances the adenoma detection rate. Water infusion in a difficult sigmoid reduces pain and improves the adenoma detection rate, but not the caecal intubation rate. The presence of a large, flat, dysplastic polyp in the left colon points to a higher risk of polypoid lesions in the proximal colon, stressing the need for standard meticulous pan-colonoscopy. Small polyps can be removed by cold-snaring or with a large calibre foreceps. Larger lesions, not suitable for snare polypectomy, are increasingly removed by endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). A meta-analysis of EMR versus ESD, involving well over 2000 polyps, showed following respective results: perforation 1.4 versus 5.7%; delayed bleeding 3.5 versus 2.0%; procedure duration 30 versus 66–108 m. Of the several (ESGE, ACG) guidelines that were discussed only a few items will be covered: regarding bowel cleansing, avoid sodium phosphate and magnesium citrate preparations in the elderly, or patients with renal disease, or those taking medications that alter renal blood flow or electrolyte excretion. Avoid metoclopramide. Offer a repeat colonoscopy within 1 y in patients with inadequate preparation. If small bowel bleeding persists, the diagnostic work-up should include a repeated upper and lower endoscopy, capsule endoscopy, balloon-enteroscopy, CT or MR enterography as appropriate. Intra-operative endoscopy should be available at the time of surgery. Patients with aortic stenosis and angioectasia (Heyde syndrome) and ongoing bleeding should undergo aortic valve replacement.
The American guidelines on surveillance after colorectal cancer surgery were also covered.
– For stage I cancer and risk factors: CEA twice/y/5 y; colonoscopy after 1 y and then every 3–5 y; 5 yearly CT or MRI. – For stage II to III cancer: CEA twice yearly for 5 y; colonoscopy after 1 y and then every 3–5 y; 5 yearly CT or MRI. – For stage IV metastatic disease; CEA twice yearly for 5 y; colonoscopy after 1 y and then every 3–5 y; 5 yearly CT or MRI.
Gastrointestinal infections Herbert Tilg Lecture – Gastro Update Europe 2016 – Prague. Some recent developments in gastrointestinal infections were summarised by Prof Herbert Tilg from Austria. First discussed was the importance of the rising outbreaks of norovirus infection, the most frequent cause of foodborn illness together with Campylobacter infection. Norovirus, a calicivirus, has a worldwide distribution (incubation period is 24–48 h), with symptoms lasting 48–72 h and viral shedding in stool continuing for 2–3 weeks. Viral identification is mandatory especially in an outbreak setting with nucleic acid based testing (RT-PCR) or immuno-assay. Vomiting is a key clinical symptom. Particular attention is required when alarm symptoms develop, such as dehydration, enteral bleeding, weight loss, severe abdominal pain, and if symptoms last longer than a week, especially in the elderly or in immunosuppressed people. End 2014, a more virulent genotype variant appeared, which is more capable of immune evasion, causing severe gastroenteritis and often necessitating hospitalisation. It is unfortunate that no antiviral therapy is available; vaccines are under development. Hand wash with soap and water for 30 s removes the virus from finger pads in contrast to washing with propanolbased hand disinfectant, which shows little viral reduction. Campylobacter infection, the most common cause of bacterial diarrhoea is largely a foodborn disease. Campylobacter inhabits the intestinal tract of many animals, most notably poultry. The incubation period lasts 3 d. The disease presents with fever, followed by abdominal cramps and diarrhoea. Late complications are reactive arthritis and Guillain Barre syndrome. Therapy focuses on rehydration; antibiotics should be limited to severe disease (ciprofloxacin, azithromycin). Most intriguing, based on a metaanalysis, is the finding that Campylobacter infection increases the risk of IBD, in contrast to H. pylori infection which seems negatively associated with IBD. This observation begs for understanding. Clostridium difficile colonises the human intestinal tract after the normal gut flora has been altered by antimicrobial therapy. The spectrum of clinical presentation is highly variable. Life threatening disease, including fulminant colitis, is possible. Testing for toxin is recommended for symptomatic patients with nosocomial infection. In a large European multicentre (482 hospitals), prospective bi-annual point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea, it was shown that because of – absence of clinical suspicion and suboptimal laboratory diagnostic methods were responsible, 40,000 European inpatients per year with Clostridium difficile infection were not diagnosed properly. Note that PCR testing will lead to overdiagnosis of Clostridium difficile infection; measuring the presence of toxin is essential for adequate diagnosis. All Clostridium difficile infection-related complications and deaths occur only in toxinpositive patients. Patients with a positive PCR, but with a negative toxin assay, had similar outcomes as patients without Clostridium difficile infection. It is also wise to remember that there is a high rate of alternative diagnoses in patients referred for presumed
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Clostridium difficile infection; indeed up to 25% of such patients have a non-Clostridium difficile diagnosis, mainly IBD and IBS. Morbidity and mortality of Clostridium difficile infection in postoperative patients is alarmingly high. Almost 500,000 post-surgical patients in well over 100 American hospitals were analysed. The Clostridium difficile infection rate was 0.4% per year. Risk factors were: age, frequently hospitalisation, complex surgery, and increased antimicrobial use. Postoperative morbidity was higher and 30 d mortality was 5.3% compared to 1.0% in non-infected patients. Therapeutic recommendations may be summarised as follows:
– moderately severe: oral metronidazole (3 500 mg) or vancomycin (4 125 mg) for 2 weeks; – severe disease: iv metronidazole: oral/nasogastral vancomycin (4 500 mg) or fidaxomicin (2 200 mg) for 2 weeks; – complicated disease: see above, plus faecal microbiota transplantation (FMT). The initial spectacular results of FMT, at first infused via the proximal intestine, have been confirmed – also infused via the colon, and in patients with very severe and complicated infection, and further in patients with toxic megacolon. The FMT technology is constantly evolving; frozen microbiota seems equally efficacious as fresh stool enemas. Microbiota suspension as enema in readyto-use format seems also safe and effective. Finally, studies are ongoing to find out if a small molecule ebselen (an anti-oxidant and antivirulence agent), targeting the cystein protein domain of toxin B, can be used clinically to control the disease. The deleteri-
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ous effects of continuous PPI therapy in recurrent Clostridium difficile infection is well established. In a recent retrospective cohort study involving some 750 patients with Clostridium difficile infection, PPIs were used in 61% (of whom only about half had an evidence-based indication!). Almost none of the PPI users stopped the drug despite the proven risk. PPI use decreases the bacterial richness and results in profound microbiome changes, affecting 20% of the bacteria. Oral/pharyngeal bacteria and potential pathogenic bacteria (enterococci, streptococci, staphylococci, micrococci, etc.) increase. Some investigators even claim that PPI induce more bacterial alterations than use of antimicrobials. Exploring the role of the gut microbiome in many diverse diseases continues, also with respect to the gut-brain interaction. As an example: evidence is increasing supporting the role of the indigenous bacteria from the gut microbiome in the regulation of serotonin biosynthesis and metabolism, impacting on gastrointestinal motility, secretion, and haemostasis. Altering the microbiota may well improve 5-hydroxy tryptamine-related disease symptoms such as IBS, but also other conditions. Obviously there is more to come. Guido N.J. Tytgat Division of Gastroenterology-Hepatology, Academic Medical Center, Meibergdreef, 1105 AZ Amsterdam, Netherlands E-mail address: [email protected] Received 18 August 2016 Accepted 18 August 2016 Available online xxxx
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Congress Report
Highlights from Gastro Update Europe – Prague, April 29–30, 2016
These highlights summarise a selection of the most important gastrointestinal discoveries of high clinical relevance presented at the recent Gastro Update Europe in Prague. The selected topics are indicative of what the faculty considered to be essential to be communicated to the astute busy gastroenterologist in clinical practice, who wants to stay abreast of clinically important developments. Whenever appropriate a personal note or comment is included to further raise the educational level of these highlights. Gastro Update Europe, a truly intense educational enterprise, presented and discussed by top opinion leaders in gastroenterology and hepatology, is a unique teaching format of yearly rising scientific quality. Disorders of the proximal digestive tract Peter Malfertheiner Lecture – Gastro Update Europe 2016 – Prague. Prof. Peter Malfertheiner from Germany reviewed the most salient recent achievements in the upper intestinal tract. Gastrooesophageal reflux disease (GERD) continues to be one of the leading diagnoses in ambulatory care both in the USA and in Europe. Proton pump inhibitors (PPI) remain by far the first drug class for the initial therapy for symptomatic GERD, with a trend to increase the dose and the frequency of dosing. Even stronger inhibition of acid secretion is possible with a so-called potassium competitive acid blocker (p-cab) such as vonoprazan. Vonoprazan binds immediately and selectively to both active and resting pumps in the parietal cell; the slow dissociation from the pump explains the long-lasting acid inhibition. Moreover, the drug is not influenced by Cyp2C19 genotype. Vonoprazan shows impressive prolonged acid secretory inhibition, so far with few if any adverse effects (in contrast to previous p-cab attempts). It is to be expected that the spectacular Japanese results will be confirmed in the West and that the drug ultimately will become available in Europe. What the proper indications and mode of administration of this superior acid suppressant will be in clinical practice will require detailed study in view of the non-negligible consequences of prolonged profound acid suppression. The use of PPIs, even very long-term, is generally considered as rather safe. Yet clinicians should remain vigilant for possible adverse effects (magnesium, vitamin B12 etc). Earlier studies pointed to a potentially enhanced risk of PPIrelated community-acquired respiratory tract infection, but in a recent retrospective analysis of over 14,000 patients, there was no causal association between esomeprazole versus placebo in
the occurrence of community-acquired respiratory tract infection and pneumonia, which is certainly reassuring. The PPI-clopidogrel controversy is fading away; indeed an updated meta-analysis was presented regarding the incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without PPIs. The myocardial infarction rate and the overall mortality were indistinguishable between the 2 groups, which again is reassuring. More annoying is perhaps the relationship between PPI use and chronic kidney disease. In a study of the risk for atherosclerosis in 10.000 community participants, PPI use (which was more common in Caucasians, the obese and users of antihypertensives) was associated with chronic kidney disease, especially with twice-daily dosing. This finding contrasts with the detailed analysis of the long-term comparison of anti-reflux surgery versus prolonged PPI therapy where essentially no laboratory abnormalities were discovered between the 2 groups. One can only speculate why some participants in the atherosclerosis study were at risk for chronic kidney disease (pre-existent latent kidney disease, pharmacological interactions, confounders, etc). Anyhow, significant laboratory anomalies are not to be expected in reflux patients on PPI monotherapy. Intriguing was a recent pharmacoepidemiologic study showing an increased risk of dementia in PPI users. Obviously a prospective randomised clinical trial is mandatory to establish a direct cause and effect relationship between PPI use and incident dementia in the elderly. Such a study will be extremely difficult to carry out, but of high clinical relevance in view of the rising dementia and PPI use in the elderly, often as a gastric mucosal protectant. Several studies analysed the (major) effects of long-term PPI use on the colonic microbiota, and especially on the rising risk of Clostridium difficile infection. There is a significantly lower abundance in gut commensals, and a lower microbial diversity in PPI users, with a significant increase in oral and upper gastrointestinal tract commensals together with increased numbers of enterococ, streptococ, staphylococ and potentially pathogenic Escherichia coli. The observed changes may well result from the removal of the low pH gastric barrier (the so-called acid steriliser). Alginate/antacids such as Gaviscon double action, active particularly in the area of the acid pocket in the upper stomach are usually used as add-on therapy for insufficiently controlled or break-through symptoms during PPI therapy for reflux control. A recent large Chinese study showed that Gaviscon (2 tablets 4 daily) as monotherapy could successfully relieve symptoms in mild to moderate GERD. It seems somewhat doubtful whether
http://dx.doi.org/10.1016/j.ajg.2016.08.002 1687-1979/Ó 2016 Published by Elsevier B.V. on behalf of Pan-Arab Association of Gastroenterology.
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such results could be confirmed in the west and whether it would change the PPI dominance as first-line therapy for GERD. Eesophageal columnar metaplasia or Barrett oesophagus, present in 1–2% of the general population and some 10% of GERD patients, continues to generate major attention largely because of the 30–40% increased risk of oesophageal adenocarcinoma. Remember that the majority of Barrett patients will not progress to cancer and that only some 5% of adenocarcinoma patients have been identified as Barrett carriers before cancer diagnosis. Is it possible to reduce the cancer risk? The overall risk of neoplastic progression can be reduced by some 30% with aspirin/NSAID therapy, by some 48% with statin therapy and by some 67% with PPI. Based on these data, many clinicians prescribe prolonged PPI therapy also in asymptomatic carriers of columnar metaplasia. Solid information upon which to base guidelines for endoscopic/bioptic surveillance (a hotly debated topic) does not exist. There is some consensus that surveillance of non-dysplastic Barrett, to decrease the risk of cancer death, should only be considered and targeted to high-risk groups: age >50 y, Caucasian, male gender, the obese, symptomatic. Also, the length of the Barrett segment is relevant. Of over 1.000 T1 adenocarcinomas, 56% occurred in long segment (>3 cm) Barrett oesophagus. The estimated annual cancer transition in long segment was 0.22%. Few would now disagree that patients with high-grade dysplasia should be amenable to preferentially endoscopic therapy (resection with radiofrequency ablation). A new American trial confirmed that patients with well established low-grade dysplasia should also be amenable to radiofrequency ablation. The annual rates of progression to high-grade dysplasia/early adenocarcinoma in that study were 6.6% in the surveillance arm compared to 0.77% in the radiofrequency arm. Eosinophilic oesophagitis remains the most intriguing novel oesophageal disorder. The rising frequency, at least in the West, is genuine. A large Danish study showed that the increased incidence and prevalence outpaces the changes in endoscopy and biopsy practice. The rise of the disease remains largely enigmatic. Insufficient microbial/parasitic allergen exposure early in life may well contribute to a predominance of a Th2- type immune response pattern later in life. A simplified pathophysiologic scheme is shown below.
D’Alessandro A et al. Pathological mechanisms underlying therapy of EoE. World J Gastrointest Pathophysiol 2015;6:150
In the traditional definition, eosinophilic oesophagitis does not respond to acid suppression. Yet many patients with eosinophilic inflammation do seem to respond to PPI therapy, the so-called PPI-responsive oesophageal eosinophilia, leading to the concept that PPI-REE was a separate entity. However, sufficient data have
been presented to show that eosinophilic oesophagitis and PPIREE are almost indistinguishable also from a genetic point of view. It would appear that in the initial and mild phases of the disease, symptoms may respond to acid inhibition. PPIs have anti-inflammatory effects, but PPI-responsiveness may gradually disappear as the fibrotic remodelling of the disease progresses. Therefore the first therapeutic approach is PPI therapy. Should PPI therapy fail, topically active corticosteroids should be tried. In a large multicentre trial budesonide effervescent tablets (twice 1 or 2 mg) or viscous suspension (twice 2 mg) were compared versus placebo, and both showed high histological remission rates. Gastrointestinal bleeding remains a major life-threatening emergency, especially in the elderly and is of major current interest in view of the rising use of the novel non-vitamin K antagonist anticoagulants (noacs). In a large population-based cohort study, the hazard ratio of gastrointestinal bleeding with dabigatran was 2.29, with rivaroxaban 2.84, and with warfarin 2.87. In patients with atrial fibrillation, the risk of bleeding with dabigatran was less compared with warfarin, except for patients older than 75 y. This was confirmed in a meta-analysis of 23 studies comparing the risk of major gastrointestinal bleeding with non-vitamin K oral anticoagulants (noac) versus warfarin, showing that the bleeding risk in atrial fibrillation was not different between noacs and vitamin K antagonists. Fortunately the risk of dabigatran-related gastrointestinal bleeding can be reduced by gastroprotective agents as shown in a population-based study where the bleeding risk was 2.5% and was lowered to about half with gastroprotective agents. Detailed analysis of 10 randomised controlled trials regarding the use of PPI in the prevention of low-dose aspirin-associated upper gastrointestinal injury led to the following conclusions: PPIs decrease the risk of low-dose aspirin-associated upper gastrointestinal ulcers with 84% and of bleeding with 73%; for patients treated with dual anti-platelet therapy of low-dose aspirin and clopidogrel, PPIs prevent bleeding in 64% without increasing the risk of major adverse cardiovascular events. Moreover, PPIs were markedly superior to H2RAs in ulcer and bleeding prevention. Protection was also shown in a nation-wide Scandinavian study which showed that the use of PPI was associated with a decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with NSAIDS. The overall age-standardised incidence of gastric cancer (8.8 per 100,000) and cardiac cancer (3.3 per 100,000) remains high with 5-y survival rates of less than 25%. Helicobacter pylori infection, especially with virulent strains, remains the leading cause through pre-neoplastic remodelling of the gastric mucosa. Ideally, H. pylori should be eradicated before the development of irreversible pre-neoplastic lesions. The risk of cancer increases from gastritis, atrophic gastritis, intestinal metaplasia and dysplasia. The Olga system is increasingly used to monitor the changes in the gastric mucosa and to estimate the cancer risk. Arguments have been presented to take an additional biopsy of the angulus next to the standard antrum and corpus biopsies as this raises the detection of atrophy and intestinal metaplasia. Since the quality of the endoscopic equipment is continuously improving, there is a trend to move away from non-targeted to targeted biopsies, directed to areas of minor abnormality, only detectable with high-definition endoscopes, with or without supplementary technologies (chromo, NBI etc). The demand for high-quality equipment such as high-definition is supported by a sobering British retrospective analysis, revealing that 8.3% of patients with gastric cancer had their malignancy missed at endoscopy carried out within the 3 previous years. Screening of high-risk individuals and subjects in high-risk areas should ideally be conducted with the so-called gastropanel (measuring gastrin17, pepsinogen I, II, and ratio, and anti-H. pylori antibodies). As already stated, ideally H. pylori eradication should
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occur before gastric mucosal neoplastic remodelling, but even after endoscopic resection of gastric neoplasia, eradication may be indicated to prevent metachronous lesions in approximately 60%, as shown in a recent meta-analysis. There is a manifest revival of bismuth-based therapy for H. pylori eradication. The Maastricht V-2016 edition recommends for areas with high (>15%) clarithromycin resistance, bismuth quadruple or non-bismuth quadruple therapy (PPI, amoxicilline, clarithromycin, nitroimidazol). In areas of high dual clarithromycin and metronidazole resistance, bismuth quadruple therapy is the recommended first line treatment. Apparently concomitant nonbismuth quadruple therapy is superior to sequential therapy. Bismuth appears to act, not by direct interaction with urease or the urea channel in the inner bacterial membrane, but by impeding proton entry in the organism. The diminished fall in cytoplasmic pH with acidification in the surrounding medium favours upregulation of the genes involved in growth, which allows augmented efficacy of the growth-dependent antimicrobials. Amoxicillin can be used instead of tetracycline in first-line bismuth quadruple therapy as shown in a large important Chinese study comparing 14 d therapy with bismuth, lansoprazole, amoxicillin, and metronidazole (cure rates 94 and 93% for metronidazole sensitive versus resistant) and bismuth, lansoprazole, amoxicillin, and clarithromycin (cure rates 99 and 77% for clarithromycin sensitive versus resistant). Overall recommendations in case of eradication failure are summarised below:
1st line
2nd line
3rd line
Regions with low ClariR prevalence
Regions with high ClariR prevalence
PPI-Clari-Amoxicillin/metronidazole or Bismuth Quadruple
Bismuth Quadruple
Bismuth Quadruple or PPI-Levofloxacin/Amoxicillin
if not available Non-Bismuth quadruple
PPI-Levofloxacin/Amoxicillin
Based on susceptibility testing only Malfertheiner et al., GUT 2012 May;61 (5):646-64 ; GUT 2016 subm
Novel eradication schemes have been attempted in case of eradication failure with non-bismuth quadruple therapy such as:
– bismuth, esomeprazole, amoxicillin, levofloxacin (cure rate 74% in highly resistant patients: amoxicillin 8%; clarithromycin 56%; metronidazole 74%; levofloxacin 36%); – bismuth quadruple; omeprazole and pylora (=bismuth subcitrate, tetracycline, metronidazole) for 10 d (cure 83% in patients with resistance to metronidazole, clarithromycin and fluoroquinolone or with multiple prior treatment failures); – adding rifabutin to pantoprazole and amoxicillin or rifabutin to pantoprazole, amoxicillin, and bismuth. More intensified acid suppression with the novel p-cab vonoprazan was shown to improve the eradication rates from 76% [lansoprazole, amoxicillin, clarithromycin] to 93% [vonoprazan,
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amoxicillin, clarithromycin] in over 600 gastroduodenal ulcer patients. Novel developments in pancreatic disorders Peter Layer Lecture – Gastro Update Europe 2016 – Prague. Prof Peter layer from Germany analysed the recent novel findings with respect to pancreatic diseases. First discussed was acute pancreatitis, still a devastating entity. Excessive alcohol intake and smoking are well established causes of chronic pancreatitis; their role in the pathogenesis of acute pancreatitis is less clear. A large case-control study compared over 500 patients with acute pancreatitis to over 10,000 matched controls. It was clearly shown that the risk of acute pancreatitis rises with rising daily alcohol intake: 50 g-3-fold; 70 g-4.2fold; 90 g-5.3fold; >100 g-6.4-fold. Also, tobacco smoking increases the risk of acute pancreatitis approximately 2-fold, as shown in a meta-analysis of 12 studies. Clinicians should therefore be aware that smoking is a potential cause of ‘idiopathic’, especially relapsing acute pancreatitis. Such patients should therefore be strongly advised to quit smoking. How smoking leads to acute pancreatitis remains poorly understood. What is also insufficiently realised in practice is that pancreatic cancer may occasionally present as acute pancreatitis. In a large American cohort with over 500,000 subjects, approximately 1 in 10 pancreatic cancers manifested first as acute pancreatitis. Most cancers became overt within 2 y post the presentation with acute pancreatitis. Whenever therefore, the cause of acute pancreatitis is not clear, meticulous EUS examination of the pancreas is indicated in order not to delay the detection of the underlying malignancy. Hypertriglyceridaemia is a well established cause of acute pancreatitis. Disease severity and risk of persistent organ failure are high, and parallel the severity of hypertriglyceridaemia: mild <200; moderate <1000; severe >1000 mg/dl. It is beyond doubt that hypertriglyceridaemia is strongly associated with severe and complicated acute pancreatitis, either as the sole aetiology or as amplifier of other causes. The involved pathogenetic mechanisms and therapeutic possibilities are insufficiently elucidated. Most intriguing is the potential preventive role of statins in the prevention of acute pancreatitis, as analysed retrospectively in 4 million Californian subjects: acute pancreatitis risk (of any cause) was some 70% reduced in statin (simvastatin) users, especially with a dose of >10 mg/d. As many confounders may be involved, these data beg for a prospective randomised study. How statins may be potentially preventive also needs further study. Up to now, there has been little consensus with respect to the timing of cholecystectomy after (mild) biliairy pancreatitis. In an important study, over 250 patients with mild biliairy pancreatitis [CRP < 100 mg/l; opiate-free pain control; oral refeeding] were randomised to immediate surgery (within 3 d of admission) versus delayed surgery (>25 d after discharge). There was a 70% decrease in relapse of biliairy symptoms and pancreatitis or death within 6 months in the Group with immediate surgery during the index hospital admission. These results are quite persuasive and deserve to be followed-up in practice. Whether and when antimicrobials should be used in acute necrotising pancreatitis remains a moot and controversial point. An earlier meta-analysis showed a 40% reduced mortality with antimicrobial therapy (betalactam, imipenem) but all studies had considerable methodological flaws and deficits. In a novel metaanalysis of 6 randomised controlled trials involving close to 400 patients with acute necrotising pancreatitis, early antimicrobial administration led to a 50% reduction in overall mortality and 45% reduction in infected necrosis. Early antimicrobial therapy
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is probably useful in individual patients with extensive necrosis or a predicted severe disease course. Previous studies have shown that oral refeeding may start early in mild, and even more severe pancreatitis, but refeeding attempts are not always successful, especially in patients with hypertriglyceridaemia or with persistently elevated enzymes (lipase >2 times the norm). It is preferred not to force oral feeding from day one but to use recurrence of appetite as a reliable indicator for successful oral refeeding. Healing of severe acute pancreatitis may be associated with morphological and functional defects. A meta-analysis of 8 follow-up studies involving 234 patients with acute pancreatitis, revealed that 43% developed diabetes mellitus, 29% pancreatic exocrine insufficiency and 40% both sequellae. Appropriate follow-up is therefore mandatory. Alcohol consumption is a well-known and established cause of chronic pancreatitis. A recent high-quality case-control study involving over 400 patients and over 1000 matched controls revealed an impressive alcohol dose–response risk; for daily alcohol intake of 30, 50, 70, 90, and >100 g, the risk for chronic pancreatitis rose from 2.8, 3.2, 9.2, 13 and 19.5 times respectively. In simple terms: daily alcohol consumption <20 g: no risk; moderate risk with linear increase at 20–60 g/d; rapid increase in risk beyond 60 g/d (>2 glasses of wine; >pints of beer). Correlation between symptom pattern and severity and morphological objective alterations is often poor in gastroenterology. The same holds for chronic pancreatitis where no correlation between pancreatic morphological changes (obstruction, inflammation, pseudocysts etc.) and symptom pattern or severity is apparent. Interest in autoimmune pancreatitis remains intense. As a reminder, there are apparently 2 types: the more frequent type 1 (IgG4-associated systemic disease, often involving multiple organs) and type 2 (isolated pancreatic disease, concomitant IBD). Type 2 has been further characterised in 43 patients: 58% presented initially as relapsing acute pancreatitis; 36% presented initially as mass lesion and obstructive jaundice (mimicking cancer); 50% had associated IBD and 11% relapsed within 3 y after treatment. Early diagnosis is essential as the prognosis is excellent with adequate (corticosteroid) therapy. There is consensus that in principle, main duct intraductal papillary mucinous neoplasm (IPMN) should be treated surgically as cancer will develop in 1 out of 3 patients within 3 y. For branch duct IPMN, surgery is indicated for lesions larger than 3 cm, diameter of the pancreatic duct >5 mm, presence of intramural nodules and suspicious cytology. A large study evaluated the survival in patients with main duct IPMN that could not be resected for various reasons: 5 y survival in the resected group was 74% versus 58% in the non-resected group; those older than 70 y had a significantly worse outcome as expected (comorbidities, reduced operability etc). Statin use was also evaluated in the survival of over 200 patients resected for early-stage pancreatic cancer. Simvastatin reduced the mortality by 44% and the relapse rate by 39% if a high dose was used. It is utterly intriguing why simvastatin may improve the prognosis following curative resection of early-stage pancreatic cancer. Prospective, high-quality studies are urgently needed to consider simvastatin use as standard adjunctive anticancer therapy.
Developments in digestive endoscopy Andrea May, Marco Bruno and Bjorn Rembacken Lectures – Gastro Update Europe 2016 – Prague. Prof Andrea May from Germany covered endoscopic achievements in the upper gastrointestinal tract.
There is no global consensus on the need and the characteristics of surveillance of patients with oesophageal columnar metaplasia (Barrett). Most would agree that surveillance is only clinically indicated when the neoplastic risk is truly enhanced. Based on a large cohort of over 1000 oesophageal early adenocarcinoma, cancer was more common in long segment Barrett (>3 cm) (56%) compared to short segment (<3 cm) metaplasia (24%). The authors conclude that the cancer incidence per 100,000 population is 3.3 for long segment compared 1.4 for short segment. Based on these findings, it would appear that Barrett length should be integrated in the surveillance advice: every 2–3 y for long segment, every 5 y for short segment. We are again reminded that surveillance is a difficult procedure, requiring optimal equipment, optimal dedication, and expertise for adequate detection of neoplasia. In a prospective surveillance study of routine clinical practice of 121 patients with Barrett neoplasia, only one third of the neoplastic lesions were correctly identified at endoscopy. The other two thirds were initially considered as non-suspicious aberrations; particularly type IIb (flat, non-elevated) were prone to misinterpretation. Because detection and proper identification of flat neoplasia is difficult, it is probably still wise to take 4-quadrant non-targeted biopsies during the index endoscopy to diminish the risk of missing neoplastic changes. Peroral endoscopic myotomy (POEM) was added to pneumodilation and laparoscopic Heller myotomy for the treatment of achalasia. The long-term results of the large multicentre prospective trial comparing pneumodilation to laparoscopic myotomy have become available. In that study, re-pneumodilation was allowed twice if this therapy was initially successful and if symptoms recurred beyond 2 y after the first pneumodilation; treatment failure was decided if symptoms recurred sooner. Respective per protocol 5 y success was 91 versus 82%, and intention-to-treat success was 82 versus 84% for pneumodilation and laparoscopic myotomy; perforation occurred in 5% after pneumodilation and mucosal injury occurred in 12% after myotomy. This study therefore illustrates that both techniques are comparable from a clinical point of view. The choice of therapy should at large be based on local expertise. Certainly in the younger patients (<40 y) myotomy by an experienced surgeon deserves to be considered. Whilst the technique of POEM continues to improve, follow-up data from the initial studies are becoming available. 80 patients from a multicentre study were followed-up for 2–3 y. The initial success rate of 96% dropped to 78% beyond 2 y of follow-up. Initial failure (4%) and disease recurrence (18%) occurred mainly during the learning phase of the procedure. Endoscopic reflux oesophagitis was diagnosed in 40% (!) of the patients, usually requiring prolonged PPI therapy. POEM is certainly an attractive novel procedure but may not be superior to the other treatment modalities, and cannot yet be recommended as the new standard therapy of choice. Endoscopic haemostasis with haemostatic powder (such as haemospray etc) continues to be explored particularly with respect to the proper indications (diffuse bleeding, difficult bleeding areas to reach, failure of other haemostatic modalities, etc. In a study with 40 patients with upper-intestinal, non-variceal bleeding, initial haemostasis was obtained with haemospray in 95% but bleeding recurred in 30%. Interestingly, no haemostatic powder was endoscopically detectable after 24 h. For the time being, haemostatic powder should be considered as a reserve method together with the standard endoscopic haemostatic modalities: injection of saline/epinephrine; mechanical clipping and ligation; thermal electrocoagulation. The number of patients on anticoagulants (vitamin-K antagonists, such as warfarin or the novel oral anticoagulants, such as dabigatran) that need an endoscopic procedure is increasing. Low risk procedures are upper and lower endoscopy + biopsy, biliary
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or pancreatic stenting, and diagnostic EUS. High risk procedures include: polypectomy, sphincterotomy, EUS with fine needle aspiration, PEG, variceal banding and stricture dilation. To prevent peri-operative bleeding, inpatients with atrial fibrillation, warfarin is usually stopped 5 d before the procedure and low-molecular weight heparin is given as peri-operative bridging. Warfarin can be resumed within 24 h after the procedure. In a large study with almost 2000 patients with atrial fibrillation, heparin was compared with placebo as bridging in patients with a mean CHAD2 score of 2, 3; arterial thromboembolism occurred in 0.3 versus 0.4% but major bleeding in 3.2 versus 1.3% respectively in the heparin versus the placebo group. The authors conclude that for low risk interventions and a CHAD2 score 62, no bridging with heparin is required and warfarin can be resumed within 2 h after the procedure at the usual dose. Currently, the CHA2DS2-VASc scoring system is often used. Following points are given: congestive heart failure 1, hypertension 1, age P75 y 2, diabetes 1, stroke 2, vascular disease 1, age 65–74 1, female gender 1. Interest in full (transmural) thickness resection of localised mural lesions throughout the gastrointestinal tract is rising, and dedicated full thickness resection devices have recently been described. Obviously such technology should be in the hand of highly experienced endoscopists, in a centre with full expertise in endoscopic emergencies, but the expectation is that such endoscopic approaches will expand. The wall defect is usually closed before transmural transection, with a large over-the-scope (OTC) clip. An alternative is to suture the defect with a suturing device (over-stich; plicator; Gerdx etc). Balloon-assisted endoscopy is increasingly performed in patients with Crohn disease. In a retrospective analysis of almost 30,000 patients examined with balloon-assisted endoscopy, the overall perforation rate was 0.1%, but the risk increased 2.5-fold in Crohn, 3-fold in steroid users and 9-fold in the latter combination. Utmost attention is therefore mandatory in the presence of ulcerated lesions and concomitant steroid therapy. A rising alternative to endoscopy is dedicated MRI enterography for primary diagnosis but also for monitoring therapy. There is even some hope that in the future, MRI-based differentiation between inflammation and fibrosis will be possible and quantifiable, which will have major impact in the choice of therapy. Prof Marco Bruno from the Netherlands covered the recent findings of clinical relevance in the biliopancreatic area with ERCP and EUS. First discussed was the role of endoscopic sphincterotomy for suspected sphincter of Oddi dysfunction, which is commonly performed in the USA. In a landmark multicentre American sham-controlled randomised trial involving over 200 patients with pain after cholecystectomy, without significant abnormalities on imaging or laboratory studies and without prior sphincter treatment or pancreatitis, sphincterotomy was compared to sham therapy with follow-up blinded lasted for 1 y. After ERCP patients were randomised irrespective of sphincter manometry findings. Those randomised to sphincterotomy with elevated pancreatic sphincter pressure were randomised again to biliary or to both biliary and pancreatic sphincterotimy. The outcome was essentially negative; sphincterotomy (either biliary or combined biliary and pancreatic) was no better than sham placebo in relieving symptoms. Physicians should therefore be utterly reluctant to carry out a (risky) sphincterotomy if in the absence of imaging or lab abnormalities. Already in a somewhat older study, it was shown that rectal NSAIDs reduce the incidence of post-ERCP pancreatitis, which occurred in 9% of the indomethacin group, compared to 17% in the placebo group. Based on such findings, it is usually recommended to administer rectally 100 mg indomethacin or diclofenac before or after ERCP, especially in patients with an elevated baseline risk [suspected sphincter of Oddi dysfunction; prior pancreatitis; precut sphincterotomy; >8 cannulation attempts; sphincter dilation; ampullec-
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tomy] or in patients with 2 or more minor criteria [age >50 y; female gender; prior recurrent pancreatitis; >3 contrast injections in the pancreatic duct; high pressure acinarisation; duct cytologic sampling]. Perhaps these recommendations for rectal NSAIDs may not be as straight forward as initially thought because of the findings in a large general practice study (with 70% at average post-ERCP pancreatitis risk) comparing 100 mg rectal indomethacin versus placebo suppository. The study did not show protection against pancreatitis, defined by new upper abdominal pain, lipase >3-fold the upper normal level, and need for hospitalisation. Putting all information together (including some recent positive studies), it is probably wise to still continue to use rectal NSAIDs in clinical practice. By the way, parenteral administration of NSAIDs has not been shown to be effective as pancreatitic prophylaxis in the past for unknown reasons. It is widely accepted that palliative drainage of malignant common bile duct obstruction should be first attempted endoscopically. Initial insertion of a 10 Fr plastic stent is recommended if the diagnosis of malignancy is not established or if expected survival is <4 m. No drug prescription is recommended to prolong stent patency. In patients with an established diagnosis of malignancy, initial insertion of a 10 mm diameter self expanding metal stent is recommended if expected survival is >4 m or whenever the cost of such a stent is less than half the ERCP cost. A recent study with over 200 patients compared stent patency for plastic stents (172 d), uncovered (288 d) and partially covered selfexpanding metal stents (299 d). Total costs per patient at the end of the follow-up period did not differ between plastic stents and metal stents. Even in patients with <3 m survival or metastatic disease, costs did not differ. Thus in the palliation of extrahepatic biliary obstruction, self expanding metal stents have a longer functional time and total costs do not differ significantly with stent type. The standard endoscopic therapy for choledocholithiasis is endoscopic sphincterotomy and basket or balloon facilitated stone extraction. Complementary techniques for removal of large or multiple stones are mechanical lithotripsie, electrohydraulic lithotripsy, cholangioscopy with (Holmium) laser lithotripsy or extracorporeal shockwave lithotripsy. To find out if it is possible to extract large (>15 mm) or multiple (>3) stones after widening the sphincterotomy opening with a large balloon, a comparative study was performed in 70 patients comparing spincterotomy with or without balloon dilation. Complete stone removal was achieved overall in respectively 100 versus 89%; in the first session in 88 versus 56%; pancreatitis occurred in 6 versus 23%; haemorrhage in 3 versus 6%; there were no perforations. Papillary large balloon dilation, with or without endoscopic sphincterotomy was retrospectively analysed in 2 other studies and revealed similar rates of large/multiple stone removal (100 versus 98%) and adverse event rates (4 versus 7%). Based on these data, American guidelines state that papillary large-balloon dilation can be used as the initial method when large common bile duct stones have been identified. If retrograde cannulation of the biliary tree fails in case of distal malignant obstruction, percutaneous transhepatic cholangiography is often attempted. The latter technique may lead to complications (bleeding, bile leak, sepsis, peritonitis) and may cause mortality (0.6–5.6%). Novel is the possibility of EUS guided transmural drainage, preferably using an all-in-one device for puncture and deployment of a partially covered metal stent or increasingly, a lumen-apposing (diabolo-type) stent. A multicentre Korean study compared EUS-guided internal versus percutaneous drainage for unresectable malignant distal biliary obstruction and inaccessible papilla. Respective technical success was 94 versus 97%, functional success was 88 versus 87%, adverse events 9 versus 31%, reintervention rate 25 versus 55%. Stent patency and overall survival were comparable. It would appear that EUS-guided internal biliary
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drainage may well become the therapy of choice in the future now that stent design and equipment continues to improve. Conflicting data have been reported regarding the clinical impact of on-site cytopathology evaluation during EUS-guided fine needle aspiration of pancreatic masses. Observational studies have suggested that the absence of on-site cytopathology is associated with a 10–15% reduction in definite diagnosis and number of adequate specimens. Because a randomised controlled trial, comparing the impact of on-site cytopathology on the diagnostic yield and overall accuracy is lacking, a large American trial was conducted involving 240 patients. Respectively with versus without on-site cytopathology revealed a median number of needle passes of 4 versus 7, inadequate specimens of 10 versus 13% and overall accuracy of 88 versus 89%. It would therefore appear that in high volume centres there is no difference in the diagnostic yield of malignancy, accuracy, procedure time and costs between patients with pancreatic masses undergoing EUS-fine needle aspiration with or without on-site cytopathology. An obvious alternative to all this would be that the endoscopist of the future obtains some basic training in cytology slide production and evaluation, but whether this is realistic remains to be seen. Prof Bjorn Rembacken (UK) analysed endoscopy in the lower gastrointestinal tract. He first discussed the important issue of bowel cleansing. Most difficult to clean are the elderly, cirrhotics, constipated and obese patients. Adding lubiprostone to the polyethylene glycol (PEG) solution does not help. A split-dose regimen gives overall better results than the day-before cleansing, but same day cleansing is even better than splitting over 2 d. The better the cleansing result, the more sessile serrated lesions and advanced adenomas are detected, and the lesser flat lesions are missed. The higher the experience, the higher the caecal intubation rate (usually somewhat lower in women and the elderly). Cap-assisted colonoscopy has been shown to improve the adenoma/polyp detection rate, especially in the right colon. Prolonging the withdrawal/observation time beyond 6 months increases the polyp detection rate but also decreases the risk of interval cancer occurring after the colonoscopy. Using a spasmolytic (often mebeverine) during the procedure may marginally improve the procedure. Endoscopic retroversion, not only in the rectum but also in the right colon enhances the adenoma detection rate. Water infusion in a difficult sigmoid reduces pain and improves the adenoma detection rate, but not the caecal intubation rate. The presence of a large, flat, dysplastic polyp in the left colon points to a higher risk of polypoid lesions in the proximal colon, stressing the need for standard meticulous pan-colonoscopy. Small polyps can be removed by cold-snaring or with a large calibre foreceps. Larger lesions, not suitable for snare polypectomy, are increasingly removed by endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). A meta-analysis of EMR versus ESD, involving well over 2000 polyps, showed following respective results: perforation 1.4 versus 5.7%; delayed bleeding 3.5 versus 2.0%; procedure duration 30 versus 66–108 m. Of the several (ESGE, ACG) guidelines that were discussed only a few items will be covered: regarding bowel cleansing, avoid sodium phosphate and magnesium citrate preparations in the elderly, or patients with renal disease, or those taking medications that alter renal blood flow or electrolyte excretion. Avoid metoclopramide. Offer a repeat colonoscopy within 1 y in patients with inadequate preparation. If small bowel bleeding persists, the diagnostic work-up should include a repeated upper and lower endoscopy, capsule endoscopy, balloon-enteroscopy, CT or MR enterography as appropriate. Intra-operative endoscopy should be available at the time of surgery. Patients with aortic stenosis and angioectasia (Heyde syndrome) and ongoing bleeding should undergo aortic valve replacement.
The American guidelines on surveillance after colorectal cancer surgery were also covered.
– For stage I cancer and risk factors: CEA twice/y/5 y; colonoscopy after 1 y and then every 3–5 y; 5 yearly CT or MRI. – For stage II to III cancer: CEA twice yearly for 5 y; colonoscopy after 1 y and then every 3–5 y; 5 yearly CT or MRI. – For stage IV metastatic disease; CEA twice yearly for 5 y; colonoscopy after 1 y and then every 3–5 y; 5 yearly CT or MRI.
Gastrointestinal infections Herbert Tilg Lecture – Gastro Update Europe 2016 – Prague. Some recent developments in gastrointestinal infections were summarised by Prof Herbert Tilg from Austria. First discussed was the importance of the rising outbreaks of norovirus infection, the most frequent cause of foodborn illness together with Campylobacter infection. Norovirus, a calicivirus, has a worldwide distribution (incubation period is 24–48 h), with symptoms lasting 48–72 h and viral shedding in stool continuing for 2–3 weeks. Viral identification is mandatory especially in an outbreak setting with nucleic acid based testing (RT-PCR) or immuno-assay. Vomiting is a key clinical symptom. Particular attention is required when alarm symptoms develop, such as dehydration, enteral bleeding, weight loss, severe abdominal pain, and if symptoms last longer than a week, especially in the elderly or in immunosuppressed people. End 2014, a more virulent genotype variant appeared, which is more capable of immune evasion, causing severe gastroenteritis and often necessitating hospitalisation. It is unfortunate that no antiviral therapy is available; vaccines are under development. Hand wash with soap and water for 30 s removes the virus from finger pads in contrast to washing with propanolbased hand disinfectant, which shows little viral reduction. Campylobacter infection, the most common cause of bacterial diarrhoea is largely a foodborn disease. Campylobacter inhabits the intestinal tract of many animals, most notably poultry. The incubation period lasts 3 d. The disease presents with fever, followed by abdominal cramps and diarrhoea. Late complications are reactive arthritis and Guillain Barre syndrome. Therapy focuses on rehydration; antibiotics should be limited to severe disease (ciprofloxacin, azithromycin). Most intriguing, based on a metaanalysis, is the finding that Campylobacter infection increases the risk of IBD, in contrast to H. pylori infection which seems negatively associated with IBD. This observation begs for understanding. Clostridium difficile colonises the human intestinal tract after the normal gut flora has been altered by antimicrobial therapy. The spectrum of clinical presentation is highly variable. Life threatening disease, including fulminant colitis, is possible. Testing for toxin is recommended for symptomatic patients with nosocomial infection. In a large European multicentre (482 hospitals), prospective bi-annual point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea, it was shown that because of – absence of clinical suspicion and suboptimal laboratory diagnostic methods were responsible, 40,000 European inpatients per year with Clostridium difficile infection were not diagnosed properly. Note that PCR testing will lead to overdiagnosis of Clostridium difficile infection; measuring the presence of toxin is essential for adequate diagnosis. All Clostridium difficile infection-related complications and deaths occur only in toxinpositive patients. Patients with a positive PCR, but with a negative toxin assay, had similar outcomes as patients without Clostridium difficile infection. It is also wise to remember that there is a high rate of alternative diagnoses in patients referred for presumed
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Clostridium difficile infection; indeed up to 25% of such patients have a non-Clostridium difficile diagnosis, mainly IBD and IBS. Morbidity and mortality of Clostridium difficile infection in postoperative patients is alarmingly high. Almost 500,000 post-surgical patients in well over 100 American hospitals were analysed. The Clostridium difficile infection rate was 0.4% per year. Risk factors were: age, frequently hospitalisation, complex surgery, and increased antimicrobial use. Postoperative morbidity was higher and 30 d mortality was 5.3% compared to 1.0% in non-infected patients. Therapeutic recommendations may be summarised as follows:
– moderately severe: oral metronidazole (3 500 mg) or vancomycin (4 125 mg) for 2 weeks; – severe disease: iv metronidazole: oral/nasogastral vancomycin (4 500 mg) or fidaxomicin (2 200 mg) for 2 weeks; – complicated disease: see above, plus faecal microbiota transplantation (FMT). The initial spectacular results of FMT, at first infused via the proximal intestine, have been confirmed – also infused via the colon, and in patients with very severe and complicated infection, and further in patients with toxic megacolon. The FMT technology is constantly evolving; frozen microbiota seems equally efficacious as fresh stool enemas. Microbiota suspension as enema in readyto-use format seems also safe and effective. Finally, studies are ongoing to find out if a small molecule ebselen (an anti-oxidant and antivirulence agent), targeting the cystein protein domain of toxin B, can be used clinically to control the disease. The deleteri-
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ous effects of continuous PPI therapy in recurrent Clostridium difficile infection is well established. In a recent retrospective cohort study involving some 750 patients with Clostridium difficile infection, PPIs were used in 61% (of whom only about half had an evidence-based indication!). Almost none of the PPI users stopped the drug despite the proven risk. PPI use decreases the bacterial richness and results in profound microbiome changes, affecting 20% of the bacteria. Oral/pharyngeal bacteria and potential pathogenic bacteria (enterococci, streptococci, staphylococci, micrococci, etc.) increase. Some investigators even claim that PPI induce more bacterial alterations than use of antimicrobials. Exploring the role of the gut microbiome in many diverse diseases continues, also with respect to the gut-brain interaction. As an example: evidence is increasing supporting the role of the indigenous bacteria from the gut microbiome in the regulation of serotonin biosynthesis and metabolism, impacting on gastrointestinal motility, secretion, and haemostasis. Altering the microbiota may well improve 5-hydroxy tryptamine-related disease symptoms such as IBS, but also other conditions. Obviously there is more to come. Guido N.J. Tytgat Division of Gastroenterology-Hepatology, Academic Medical Center, Meibergdreef, 1105 AZ Amsterdam, Netherlands E-mail address: [email protected] Received 18 August 2016 Accepted 18 August 2016 Available online xxxx