Short- and Long-Term Outcomes After Multimodal Treatment of Pancreatic Duct Leakage in Patients With Chronic Pancreatitis.

OBJECTIVES: In patients with chronic pancreatitis, pancreatic duct leakage is associated with a prolonged disease course and serious complications. We aimed to assess the efficacy of this multimodal treatment of pancreatic duct leakage. METHODS: In a retrospective design, patients with chronic pancreatitis, an amylase content greater than 200 U/L in either ascites or pleural fluid and treated between 2011 and 2020, were evaluated. The primary end point was treatment success. RESULTS: Twenty-seven patients (22 males, median age 60, median American Society of Anesthesiologists score 3) were included.Endoscopic retrograde pancreatography was performed in 23 patients (85%) with transpapillary stenting of the main pancreatic duct in 22 patients (96%). Pancreatic sphincterotomy and dilation of the main pancreatic duct were done in 14 patients (61%) and 17 patients (74%), respectively. Twelve patients (44%) were treated with somatostatin analogs, parenteral nutrition, and were "nil by mouth" for a median of 11 days (range, 4-34 days). Six patients (22%) had extracorporeal shock wave lithotripsy due to pancreatic duct stones. One patient (4%) was referred for surgery. All 23 patients (100%) were treated with success after a median of 21 days (range, 5-80 days). CONCLUSIONS: Multimodal treatment of pancreatic duct leakage is effective, with minimal need for surgery.

Patient reported exposure to smoking and alcohol abuse are associated with pain and other complications in patients with chronic pancreatitis.

BACKGROUND/OBJECTIVES: Smoking and alcohol abuse are established risk factors for chronic pancreatitis (CP). Few studies have examined how exposure to smoking and alcohol abuse act as risk factors for complications in CP. Our aim was to examine associations between patient reported exposure to smoking and alcohol abuse and complications in CP in a large cohort of patients from the Scandinavian and Baltic countries. METHODS: We retrieved data on demographics, CP related complications and patients' histories of exposure to smoking and alcohol abuse from the Scandinavian Baltic Pancreatic Club database. Associations were investigated by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals. RESULTS: A complete history of smoking and alcohol exposure was available for 932 patients. In multivariate regression analyses, the presence of pain and exocrine pancreatic insufficiency were both significantly associated with history of smoking (OR 1.94 (1.40-2.68), p < 0.001 and OR 1.89 (1.36-2.62), p < 0.001, respectively) and alcohol abuse (OR 1.66 (1.21-2.26), p = 0.001 and 1.55 (1.14-2.11), p = 0.005, respectively). Smoking was associated with calcifications (OR 2.89 (2.09-3.96), p < 0.001), moderate to severe ductal changes (OR 1.42 (1.05-1.92), p = 0.02), and underweight (OR 4.73 (2.23-10.02), p < 0.001). History of alcohol abuse was associated with pseudocysts (OR 1.38 (1.00-1.90) p = 0.05) and diabetes mellitus (OR 1.44 (1.03-2.01), p = 0.03). There were significantly increased odds-ratios for several complications with increasing exposure to smoking and alcohol abuse. CONCLUSION: Smoking and alcohol abuse are both independently associated with development of complications in patients with CP. There seems to be a dose-dependent relationship between smoking and alcohol abuse and complications in CP.

Polymorphisms in the NFkB, TNF-alpha, IL-1beta, and IL-18 pathways are associated with response to anti-TNF therapy in Danish patients with inflammatory bowel disease.

BACKGROUND: Anti-tumor necrosis factor-α (TNF-α) is used for the treatment of severe cases of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. We have previously investigated whether single nucleotide polymorphisms (SNPs) in genes involved in inflammation were associated with response to anti-TNF therapy among patients with CD or UC. AIM: A new cohort of patients was established for replication of the previous findings and to identify new SNPs associated with anti-TNF response. METHODS: Fifty-three SNPs assessed previously in cohort 1 (482 CD and 256 UC patients) were genotyped in cohort 2 (587 CD and 458 UC patients). The results were analysed using logistic regression (adjusted for age and gender). RESULTS: Ten SNPs were associated with anti-TNF response either among patients with CD (TNFRSF1A(rs4149570) (OR: 1.92, 95% CI: 1.02-3.60, P = 0.04), IL18(rs187238) (OR: 1.35, 95% CI: 1.00-1.82, P = 0.05), and JAK2(rs12343867) (OR: 1.35, 95% CI: 1.02-1.78, P = 0.03)), UC (TLR2(rs11938228) (OR: 0.55, 95% CI: 0.33-0.92, P = 0.02), TLR4(rs5030728) (OR: 2.23, 95% CI: 1.24-4.01, P = 0.01) and (rs1554973) (OR: 0.49, 95% CI: 0.27-0.90, P = 0.02), NFKBIA(rs696) (OR: 1.45, 95% CI: 1.06-2.00, P = 0.02), and NLRP3(rs4612666) (OR: 0.63, 95% CI: 0.44-0.91, P = 0.01)) or in the combined cohort of patient with CD and UC (IBD) (TLR4(rs5030728) (OR: 1.46, 95% CI: 1.01-2.11, P = 0.04) and (rs1554973)(OR: 0.80, 95% CI: 0.65-0.98, P = 0.03), NFKBIA(rs696) (OR: 1.25, 95% CI: 1.01-1.54, P = 0.04), NLRP3(rs4612666) (OR: 0.73, 95% CI: 0.57-0.95, P = 0.02), IL1RN(rs4251961) (OR: 0.81, 95% CI: 0.66-1.00, P = 0.05), IL18(rs1946518) (OR: 1.24, 95% CI: 1.01-1.53, P = 0.04), and JAK2(rs12343867) (OR: 1.24, 95% CI: 1.01-1.53, P = 0.04)). CONCLUSIONS: The results support that polymorphisms in genes involved in the regulation of the NFκB pathway (TLR2, TLR4, and NFKBIA), the TNF-α signalling pathway (TNFRSF1A), and other cytokine pathways (NLRP3, IL1RN, IL18, and JAK2) were associated with response to anti-TNF therapy. Our multi-SNP model predicted response rate of more than 82% (in 9% of the CD patients) and 75% (in 15% of the UC patients), compared to 71% and 64% in all CD and UC patients, respectively. More studies are warranted to predict response for use in the clinic.

Chronic Pancreatitis Is Characterized by Distinct Complication Clusters That Associate With Etiological Risk Factors.

OBJECTIVES: Chronic pancreatitis (CP) is characterized by several disease-related complications and multiple etiological risk factors. Past studies of associations between complications and risk factors have mostly been limited to single complications or highly focused on single etiologies. Using an objective data-driven approach (cluster analysis), we characterized complication clusters and their associations with etiological risk factors in a large cohort of patients with CP. METHODS: This was a multicenter, cross-sectional study including 1,071 patients with CP from the Scandinavian and Baltic countries. Complications to CP were classified according to the M-ANNHEIM system, and treelet transform was used to derive complication clusters. Cluster complication frequencies were analyzed for their association with main etiological risk factors (smoking and alcohol). RESULTS: The mean age of participants was 57 years and 66% were men. Alcohol (55%) and smoking (53%) were the most common etiological risk factors and seen in combination in 36% of patients. Cluster analysis identified 3 distinct complication clusters characterized by inflammation, fibrosis, and pancreatic insufficiencies. An independent association between inflammatory complications and alcoholic etiology was seen (odds ratio [OR] 2.00 [95% CI [confidence interval], 1.38-2.90], P < 0.001), whereas smoking was associated with fibrosis-related complications (OR 2.23 [95% CI, 1.56-2.3.20], P < 0.001) and pancreatic insufficiencies (OR 1.42 [95% CI, 1.00-2.01], P = 0.046). DISCUSSION: Three distinctive clusters of complications to CP were identified. Their differing associations with alcoholic and smoking etiology indicate distinct underlying disease mechanisms.

Extracorporeal shock wave lithotripsy for pancreatic duct stones: an observational study.

INTRODUCTION: Previous studies suggest that fragmentation of pancreatic duct stones (PDS) using extracorporeal shock wave lithotripsy (ESWL) is associated with pain relief. However, the treatment may not be effective in certain subgroups. AIM: To evaluate predictors of pain relief after ESWL in patients with chronic pancreatitis and PDS. METHODS: Retrospective study including patients with chronic pancreatitis undergoing ESWL for painful PDS. Analgesic use before and after the ESWL procedure was registered. We defined adequate pain relief after ESWL as 'pain-free without analgesics or with use of weak analgesics as needed'. The study was approved by the Danish Data Protection Agency (approval number: AHH-2017-048). RESULTS: We included 81 patients (median age 58 years; 63% men; 68% alcoholic pancreatitis). Patients underwent one to seven ESWL procedures (mean 1.7). A concurrent ERCP was performed in 17%. All patients used analgesics before the ESWL procedure (68 used opioids). After ESWL, 43 still used opioids. Thirty-two patients achieved adequate pain relief. Univariable regression analysis showed that older age predicted adequate pain relief (OR 1.09;1.03-1.16; p = .002) as did location of the stone in the head or neck (OR 2.59;1.04-6.45; p = .041). In multivariable analysis, we found that the only two predictors of adequate pain relief were age (p = .002) and the location of the stones (p = .039). CONCLUSION: After the ESWL, about four out of ten patients are pain-free without medication or able to manage their pain with weak analgesics. Age and the location of the stones may be considered when evaluating if patients are eligible for referral to ESWL.

Evaluation of local instillation of antibiotics in infected walled-off pancreatic necrosis.

BACKGROUND: Infected walled-off pancreatic necrosis (WON) is associated with increased morbidity and mortality. Systemic antibiotics are the main treatment, but are associated with adverse reactions and risk of superinfections. This study evaluates the efficacy of local instillation of antibiotics into WON. METHODS: We performed a retrospective cohort study of all consecutive patients with infected WON, who were treated with endoscopic transmural drainage and necrosectomy (ETDN) at a tertiary referral hospital between 2012 and 2016. A total of 91 patients were included. Patients often received concomitant intravenous and local antibiotics. Local antibiotics were added to the irrigation fluid depending on microbiological findings. A beneficial response was defined as the eradication of a microbe on subsequent culturing. Univariable and multivariable logistic regression analyses were used to evaluate antimicrobial efficacy. RESULTS: At the first drainage 81 (86%) patients had infected and 10 sterile WON. Among patients with bacterial infections, neither local nor systemic antibiotics were associated with the eradication of microbes between first and second culture. Between the second and third culture, the use of local antibiotics was associated with the eradication of microbes (OR, 2.54; 95% CI, 1.25-5.18; p = 0.01), but not systemic antibiotics (OR, 0.75; 95% CI, 0.38-1.38; p = 0.33). Twelve patients had fungal infections treated with local amphotericin B between first and second culture. The fungus was eradicated in all 12 patients. CONCLUSION: Local instillation of antibiotics may be a promising supplement to systemic administration.

Fungal Infections in Patients With Walled-off Pancreatic Necrosis.

OBJECTIVES: This study aimed to evaluate the influence of fungal infection and antifungal treatment on outcome in patients with walled-off pancreatic necrosis (WON). METHODS: A retrospective description of fungal infections in a cohort of consecutive patients undergoing endoscopic, transmural drainage and necrosectomy for WON, treated in a tertiary referral center was reviewed. RESULTS: Between 2005 and 2013, fungal infection in WON was documented in 57 (46%) of 123 patients. The most common isolates at first positive culture were Candida albicans (55%) and Candida glabrata (20%). Thirty-nine (70%) patients were treated with antifungals after the first fungal finding. There was no significant difference in mortality (21% vs 13%, P = 0.517) or organ failure (34% vs 33%, P = 0.903) between the group treated with adequate antifungals after the first fungal finding compared to the group not treated or treated inadequately.The in-hospital mortality was 18% (10 patients). Concomitant fungemia was found in 6 patients, of which 3 died, as opposed to 7 with fungi in the necrosis only (50% vs 14%, P = 0.027). CONCLUSIONS: This study demonstrates a high incidence and associated high in-hospital mortality of fungal infection in WON, thus emphasizing the importance of fungal infections in WON.

Polymorphisms in the Toll-Like Receptor and the IL-23/IL-17 Pathways Were Associated with Susceptibility to Inflammatory Bowel Disease in a Danish Cohort.

BACKGROUND: The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Previous studies have shown that polymorphisms in the Toll-like receptor (TLR), the apoptosis, the IL-23/IL-17 and the interferon gamma (IFNG) pathways are associated with risk of both CD and UC. METHODS: Using a candidate gene approach, 21 functional single nucleotide polymorphisms (SNPs) in 15 genes were assessed in a clinical homogeneous group of severely diseased ethnic Danish patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression. RESULTS: The polymorphisms TLR5 (rs5744174) and IL12B (rs6887695) were associated with risk of CD, and TLR1 (rs4833095) and IL18 (rs187238) were associated with risk of both CD and UC (p<0.05). After Bonferroni correction for multiple testing, the homozygous variant genotype of TLR1 743 T>C (rs4833095) was associated with increased risk CD (OR: 3.15, 95% CI: 1.59-6.26, p = 0.02) and CD and UC combined (OR: 2.96, 95% CI: 1.64-5.32, p = 0.005). CONCLUSION: Our results suggest that genetically determined high activity of TLR1 and TLR5 was associated with increased risk of both CD and UC and CD, respectively. This supports that the host microbial composition or environmental factors in the gut are involved in risk of IBD. Furthermore, genetically determined high activity of the IL-23/IL-17 pathway was associated with increased risk of CD and UC. Overall, our results support that genetically determined high inflammatory response was associated with increased risk of both CD and UC.

Effectiveness of anti-tumour necrosis factor-α therapy in Danish patients with inflammatory bowel diseases.

INTRODUCTION: The objective of this study was to evaluate the outcome of anti-tumour necrosis factor-α (anti-TNF) treatment in a large cohort of patients with inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) in clinical practice and to establish a cohort for future studies of genetic markers associated with treatment response. METHODS: A national, clinically based cohort of previously naïve anti-TNF treated patients from 18 medical departments was established. The patients were screened for tuberculosis prior to treatment initiation. By combining the unique personal identification number of Danish citizens (the CPR number) from blood samples with data from the National Patient Registry, patients with International Classification of Diseases, Version 10 (ICD-10) codes K50-K63 were identified. Treatment efficacy reflected the maximum response within 22 weeks. RESULTS: Among 492 patients with CD and 267 patients with UC, 74%/13%/14% and 65%/12%/24% were responders, partial responders and non-responders to anti-TNF therapy, respectively. More patients with UC than with CD were non-responders (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.34-2.87, p = 0.001). Young age was associated with a beneficial response (p = 0.03), whereas smoking ≥ 10 cigarettes/day was associated with non-response among patients with CD (OR = 2.33, 95% CI: 1.13-4.81, p = 0.03). CONCLUSION: In this clinically based cohort of Danish patients with IBD treated with anti-TNF, high response rates were found. Heavy smoking was associated with non-response, whereas young age at treatment initiation was associated with a beneficial response among patients with CD. Thus, the results obtained in this cohort recruited from clinical practice were similar to those previously obtained in clinical trials. FUNDING: The work was funded by Health Research Fund of Central Denmark Region, Colitis-Crohn Foreningen and the University of Aarhus (PhD grant). TRIAL REGISTRATION: Clinicaltrials NCT02322008.

Endoscopic, transmural drainage and necrosectomy for walled-off pancreatic and peripancreatic necrosis is associated with low mortality--a single-center experience.

OBJECTIVE: Endoscopic transmural drainage and necrosectomy (ETDN) is a promising alternative to percutaneous drainage and surgical intervention in the treatment of walled-off pancreatic and peripancreatic necroses (WONs). We assessed the outcome and safety profile of ETDN in a single-center patient cohort. MATERIALS AND METHODS: In November 2005, ETDN for WON was introduced in our tertiary referral center. During a 6-year period (Nov 2005-Nov 2011), we retrospectively collected data on all patients who underwent ETDN. RESULTS: Eighty-one patients were treated with ETDN (median age 54, 52 men). Gallstones were the predominant etiology of pancreatitis (41%), followed by alcohol (33%). Median time from debut of symptoms to first endoscopic treatment was 44 (9-246) days. Culture-proven infected necrosis was found in 71% of the cases. Twenty-three patients (28%) required admission in intensive care unit. The technical and clinical success rates were 99% and 89%, respectively. Procedure-related complications occurred in 10 (12%) patients, of which 1 was procedure-related death. In-hospital mortality was 11%. CONCLUSION: ETDN in patients with necrotizing pancreatitis and infected necrosis performed in a single, high-volume center has an acceptable safety profile and is associated with a low mortality.

Spectrum of microorganisms in infected walled-off pancreatic necrosis - impact on organ failure and mortality.

OBJECTIVE: Data on the microbial spectrum in infected pancreatic necrosis are scarce. Only few studies have addressed this issue in a larger, consecutive group of patients treated by a standardized algorithm. Since 2005 endoscopic, transmural drainage and necrosectomy (ETDN) has been the treatment of choice for walled-off necrosis in our centre. The present study evaluated the microbial spectrum of infected pancreatic necrosis and the possible relationship between infected necrosis, organ failure, and mortality. Furthermore, we investigated whether the aetiology of pancreatitis, use of external drainage, and antibiotic treatment influenced the microbial findings. METHODS: Retrospective review of medical charts on 78 patients who underwent ETDN in our tertiary referral centre between November 2005 and November 2011. RESULTS: Twenty-four patients (31%) developed one or more organ failures, 23 (29%) needed treatment in the intensive care unit (ICU), and 9 (11%) died during hospital admission. The prevailing microbial findings at the index endoscopy were enterococci (45%), enterobacteriaceae (42%), and fungi (22%). There was a significant association between the development of organ failure (p < 0.001), need of treatment in ICU (p < 0.002), in-hospital mortality (p = 0.039) and infected necrosis at the time of index endoscopy. Enterococci (p < 0.0001) and fungi (p = 0.01) were found more frequently in patients who died during admission as compared to survivors. CONCLUSION: Different microbes in pancreatic necrosis may influence the prognosis. We believe that a detailed knowledge on the microbial spectrum in necrotizing pancreatitis may be utilized in the treatment to improve the outcome.

Polymorphisms in the inflammatory pathway genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG are associated with susceptibility of inflammatory bowel disease in a Danish cohort.

BACKGROUND: The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage. METHODS: Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in a clinical homogeneous group of severely diseased patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression. RESULTS: Sixteen polymorphisms in 13 genes involved in regulation of inflammation were associated with risk of CD and/or UC (p ≤ 0.05). The polymorphisms TLR2 (rs1816702), NFKB1 (rs28362491), TNFRSF1A (rs4149570), IL6R (rs4537545), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk of CD and the polymorphisms TLR2 (rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs352139), LY96 (rs11465996), NFKBIA (rs696), TNFA (rs1800629), TNFRSF1A (rs4149570), IL10 (rs3024505), IL23R (rs11209026), PTPN22 (rs2476601) and PPARG (rs1801282) were associated with risk of UC. When including all patients (IBD) the polymorphisms TLR2 (rs4696480 and rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs187084), TNFRSF1A (rs4149570), IL6R (rs4537545), IL10 (rs3024505), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk. After Bonferroni correction for multiple testing, both the homozygous and the heterozygous variant genotypes of IL23R G>A(rs11209026) (OR(CD,adj): 0.38, 95% CI: 0.21-0.67, p = 0.03; OR(IBD,adj) 0.43, 95% CI: 0.28-0.67, p = 0.007) and PTPN22 1858 G>A(rs2476601) (OR(CD,unadj) 0.54, 95% CI: 0.41-0.72, p = 7*10-4; OR(IBD,unadj): 0.61, 95% CI: 0.48-0.77, p = 0.001) were associated with reduced risk of CD. CONCLUSION: The biological effects of the studied polymorphisms suggest that genetically determined high inflammatory response was associated with increased risk of CD. The many SNPs found in TLRs suggest that the host microbial composition or environmental factors in the gut are involved in risk of IBD in genetically susceptible individuals.

Importance of post-treatment follow-up to secure sufficient eradication therapy for Helicobacter pylori.

INTRODUCTION: To optimize the care for Helicobacter pylori-associated diseases, we wanted to evaluate the completeness of follow-up after H. pylori eradication therapy in a single Danish endoscopy unit. Furthermore, the eradication rates and possible clinical characteristics associated with failure of eradication therapy were considered. MATERIAL AND METHODS: Patients who tested positive for H. pylori infection using a rapid urease test (RUT) during a three-year period were evaluated retrospectively according to demographics, eradication rate, type of eradication therapy, endoscopic findings and number of former attempts of eradication therapy. RUT-positive patients without a post-treatment evaluation were invited for a urea breath test. RESULTS: The overall H. pylori infection rate was 15% (117/796). Only 48/105 (46%) patients had a post-treatment examination to test the effect of H. pylori eradication therapy. The eradication rate by first-line therapy was 75% (58/77). The second-line eradication rate was 87%. 94% (72/77) had the recommended standard triple therapy for first-line eradication therapy. The number of former eradication attempts was the only clinical characteristic that significantly predicted failure of eradication therapy. Among patients with H. pylori-positive peptic ulcer, 21/28 (75%) achieved successful eradication after first-line treatment. CONCLUSION: Organised follow-up regimes are recommended, especially in patients with absolute treatment indications with a view to optimizing the care for patients infected with H. pylori.