Gastrointestinal symptoms and complications in patients hospitalized due to COVID-19, an international multicentre prospective cohort study (TIVURON project) / Síntomas y complicaciones gastrointestinales en pacientes hospitalizados por COVID-19, estudio internacional, multicéntrico, de cohorte, prospectivo (proyecto TIVURON)

Background: Retrospective studies suggest that coronavirus disease (COVID-19) commonly involves gastrointestinal (GI) symptoms and complications. Our aim was to prospectively evaluate GI manifestations in patients hospitalized for COVID-19. Methods: This international multicentre prospective cohort study recruited COVID-19 patients hospitalized at 31 centres in Spain, Mexico, Chile, and Poland, between May and September 2020. Patients were followed-up until 15 days post-discharge and completed comprehensive questionnaires assessing GI symptoms and complications. A descriptive analysis as well as a bivariate and multivariate analysis were performer using binary logistic regression. p<0.05 was considered significant. Results: Eight hundred twenty-nine patients were enrolled; 129 (15.6%) had severe COVID-19, 113 (13.7%) required ICU admission, and 43 (5.2%) died. Upon admission, the most prevalent GI symptoms were anorexia (n=413; 49.8%), diarrhoea (n=327; 39.4%), nausea/vomiting (n=227; 27.4%), and abdominal pain (n=172; 20.7%), which were mild/moderate throughout the disease and resolved during follow-up. One-third of patients exhibited liver injury. Non-severe COVID-19 was associated with ≥2 GI symptoms upon admission (OR 0.679; 95% CI 0.464–0.995; p=0.046) or diarrhoea during hospitalization (OR 0.531; 95% CI 0.328–0.860; p=0.009). Multivariate analysis revealed that worse hospital outcomes were not independently associated with liver injury or GI symptoms. Conclusion: GI symptoms were more common than previously documented, and were mild, rapidly resolved, and not independently associated with COVID-19 severity. Liver injury was a frequent complication in hospitalized patients not independently associated with COVID-19 severity.

Antecedentes: Estudios retrospectivos evidencian que la enfermedad por coronavirus (COVID-19) conlleva síntomas y complicaciones gastrointestinales (GI). Nuestro objetivo fue evaluar prospectivamente las manifestaciones GI de pacientes hospitalizados por COVID-19. Métodos: Estudio internacional, multicéntrico, de cohorte, prospectivo, que seleccionó a pacientes con COVID-19 en 31 centros de España, México, Chile y Polonia, entre mayo-septiembre de 2020. Los pacientes fueron seguidos hasta 15 días tras el alta y completaron cuestionarios que evaluaban los síntomas y complicaciones GI. Se realizó un análisis descriptivo, bivariante y multivariante de los resultados. Se consideró significativa p<0,05. Resultados: Se incluyeron 829 pacientes; 129 (15,6%) presentaron COVID-19 grave, 113 (13,7%) requirieron ingreso en UCI y 43 (5,2%) fallecieron. Al ingreso, los síntomas GI más prevalentes fueron anorexia (n=413; 49,8%), diarrea (n=327; 39,4%), náuseas/vómitos (n=227; 27,4%) y dolor abdominal (n=172; 20,7%), que resultaron de intensidad leve/moderada y se resolvieron durante el seguimiento. Un tercio de los pacientes presentaron daño hepático. La COVID-19 no grave se asoció con la presencia de ≥2 síntomas GI al ingreso (OR 0,679; IC 95%: 0,464-0,995; p=0,046) y/o diarrea durante la hospitalización (OR 0,531; IC 95%: 0,328-0,860; p=0,009). El análisis multivariante reveló que los peores resultados hospitalarios no se asociaron de forma independiente con el daño hepático o los síntomas GI. Conclusión: Los síntomas GI fueron más frecuentes de lo que se había documentado, resultaron leves, se resolvieron rápidamente y no se asociaron de forma independiente con COVID-19 grave. El daño hepático fue una complicación frecuente en los pacientes hospitalizados que no se asoció de forma independiente con COVID-19 grave.(AU)

Machine learning for the prediction of post-ERCP pancreatitis risk: A proof-of-concept study.

BACKGROUND: Predicting Post-Endoscopic Retrograde Cholangiopancreatography (ERCP) pancreatitis (PEP) risk can be determinant in reducing its incidence and managing patients appropriately, however studies conducted thus far have identified single-risk factors with standard statistical approaches and limited accuracy. AIM: To build and evaluate performances of machine learning (ML) models to predict PEP probability and identify relevant features. METHODS: A proof-of-concept study was performed on ML application on an international, multicenter, prospective cohort of ERCP patients. Data were split in training and test set, models used were gradient boosting (GB) and logistic regression (LR). A 10-split random cross-validation (CV) was applied on the training set to optimize parameters to obtain the best mean Area Under Curve (AUC). The model was re-trained on the whole training set with the best parameters and applied on test set. Shapley-Additive-exPlanation (SHAP) approach was applied to break down the model and clarify features impact. RESULTS: One thousand one hundred and fifty patients were included, 6.1% developed PEP. GB model outperformed LR with AUC in CV of 0.7 vs 0.585 (p-value=0.012). GB AUC in test was 0.671. Most relevant features for PEP prediction were: bilirubin, age, body mass index, procedure time, previous sphincterotomy, alcohol units/day, cannulation attempts, gender, gallstones, use of Ringer's solution and periprocedural NSAIDs. CONCLUSION: In PEP prediction, GB significantly outperformed LR model and identified new clinical features relevant for the risk, most being pre-procedural.

Gastrointestinal symptoms and complications in patients hospitalized due to COVID-19, an international multicentre prospective cohort study (TIVURON project).

BACKGROUND: Retrospective studies suggest that coronavirus disease (COVID-19) commonly involves gastrointestinal (GI) symptoms and complications. Our aim was to prospectively evaluate GI manifestations in patients hospitalized for COVID-19. METHODS: This international multicentre prospective cohort study recruited COVID-19 patients hospitalized at 31 centres in Spain, Mexico, Chile, and Poland, between May and September 2020. Patients were followed-up until 15 days post-discharge and completed comprehensive questionnaires assessing GI symptoms and complications. A descriptive analysis as well as a bivariate and multivariate analysis were performer using binary logistic regression. p<0.05 was considered significant. RESULTS: Eight hundred twenty-nine patients were enrolled; 129 (15.6%) had severe COVID-19, 113 (13.7%) required ICU admission, and 43 (5.2%) died. Upon admission, the most prevalent GI symptoms were anorexia (n=413; 49.8%), diarrhoea (n=327; 39.4%), nausea/vomiting (n=227; 27.4%), and abdominal pain (n=172; 20.7%), which were mild/moderate throughout the disease and resolved during follow-up. One-third of patients exhibited liver injury. Non-severe COVID-19 was associated with ≥2 GI symptoms upon admission (OR 0.679; 95% CI 0.464-0.995; p=0.046) or diarrhoea during hospitalization (OR 0.531; 95% CI 0.328-0.860; p=0.009). Multivariate analysis revealed that worse hospital outcomes were not independently associated with liver injury or GI symptoms. CONCLUSION: GI symptoms were more common than previously documented, and were mild, rapidly resolved, and not independently associated with COVID-19 severity. Liver injury was a frequent complication in hospitalized patients not independently associated with COVID-19 severity.

Early postoperative complications after gastric bypass revisional surgery in patients with previous sleeve gastrectomy versus primary gastric bypass.

BACKGROUND: Revisional bariatric surgery (RS) is indicated if there is weight regain or insufficient weight loss, no improvement or reappearance of co-morbidities, or previous bariatric surgery complications. It has been associated with higher postoperative morbidity. OBJECTIVE: To evaluate the early postoperative complications (<30 d) of Roux-en-Y gastric bypass RS (RYGB-RS) after primary sleeve gastrectomy (SG-1) compared with primary RYGB (RYGB-1) at a bariatric surgery referral center. SETTING: Department of General and Digestive Surgery of General Universitary Hospital of Alicante, Spain. METHODS: Retrospective cohort study comparing RYGB-RS after SG-1 and RYGB-1 between January 2008 and March 2021. Postoperative complications, hospital stay, mortality, and readmissions were analyzed. RESULTS: Six hundred and twenty-eight RYGB surgeries (48 RYGB-RS, 580 RYGB-1) were studied. The mean age of patients undergoing RYGB-RS was 50 years, compared with 46 years in the RYGB-1 group (P = .017). Mean initial body mass index was 44.2 kg/m2 (RYGB-RS) versus 47.6 kg/m2 (RYGB-1; P = .004). Cardiovascular risk factors were higher in the RYGB-1 group (P < .05). Indications for RS were weight regain or insufficient weight loss (72.9%), weight regain or insufficient weight loss plus gastroesophageal reflux disease (14.6%), and gastroesophageal reflux disease (12.5%). There were no differences in the frequency of complications (RYGB-RS 22.9% vs RYGB-1 20.5%) or in their severity (Clavien-Dindo ≥IIIa; RYGB-RS 10.4% vs RYGB-1 6.4%; P > .05). There were no differences in emergency room visits (RYGB-RS at 12.5% vs RYGB-1 at 14.9%) or in readmissions (RYGB-RS at 12.5% vs RYGB-1 at 9.4%). CONCLUSION: No differences were observed between primary RYGB and revisional RYGB in early morbidity, mortality, emergencies, or readmissions. Revisional bariatric surgery is a safe procedure at referral centers and must be done by expert hands.

Inflammatory capacity of exosomes released in the early stages of acute pancreatitis predicts the severity of the disease.

As acute pancreatitis progresses to the severe form, a life-threatening systemic inflammation is triggered. Although the mechanisms involved in this process are not yet well understood, it has been proposed that circulating exosomes may be involved in the progression of inflammation from the pancreas to distant organs. Here, the inflammatory capacity and protein profile of plasma exosomes obtained during the first 24 h of hospitalization of patients diagnosed with acute pancreatitis were characterized and compared with the final severity of the disease. We found that the final severity of the disease strongly correlates with the inflammatory capacity of exosomes in the early stages of acute pancreatitis. Exosomes isolated from patients with mild pancreatitis had no effect on macrophages, while exosomes isolated from patients with severe pancreatitis triggered NFκB activation, TNFα and IL1ß expression, and free radical generation. To delve deeper into the mechanism involved, we performed a proteomic analysis of the different exosomes that allowed us to identify different groups of proteins whose concentration was also correlated with the clinical classification of pancreatitis. In particular, an increase in the amount of S100A8 and S100A9 carried by exosomes of severe pancreatitis suggests that the mechanism of action of exosomes is mediated by the effect of these proteins on NADPH oxidase. This enzyme is activated by S100A8/S100A9, thus generating free radicals and promoting an inflammatory response. Along these lines, we observed that inhibition of this enzyme abolished all the pro-inflammatory effects of exosomes from severe pancreatitis. All this suggests that the systemic effects, and therefore the final severity of acute pancreatitis, are determined by the content of circulating exosomes generated in the early hours of the process. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Chronic use of statins and acetylsalicylic acid and incidence of post-endoscopic retrograde cholangiopancreatography acute pancreatitis: A multicenter, prospective, cohort study.

OBJECTIVES: Post-endoscopic retrograde cholangiopancreatography (ERCP) acute pancreatitis (PEP) is a frequent complication of this endoscopic procedure. Chronic statin intake has been linked to lower incidence and severity of acute pancreatitis (AP). Periprocedural rectal administration of non-steroidal anti-inflammatory drugs is protective against PEP, but the role of chronic acetylsalicylic acid (ASA) treatment is unclear. We aimed to investigate whether statins and chronic ASA intake are associated with lower risk of PEP. METHODS: An international, multicenter, prospective cohort study. Consecutive patients undergoing ERCP in seven European centers were included. Patients were followed-up to detect those with PEP. Multivariate analysis by means of binary logistic regression was performed, and adjusted odds ratios (aORs) were calculated. RESULTS: A total of 1150 patients were included, and 70 (6.1%) patients developed PEP. Among statins users, 8.1% developed PEP vs. 5.4% among non-users (P = 0.09). Multivariate analysis showed no association between statin use and PEP incidence (aOR 1.68 (95% CI 0.94-2.99, P = 0.08)). Statin use had no effect on severity of PEP, being mild in 92.0% of statin users vs. 82.2% in non-statin users (P = 0.31). Chronic ASA use was not associated with PEP either (aOR 1.02 (95% CI 0.49-2.13), P = 0.96). Abuse of alcohol and previous endoscopic biliary sphincterotomy were protective factors against PEP, while >1 pancreatic guidewire passage, normal bilirubin values, and duration of the procedure >20 minutes, were risk factors. CONCLUSIONS: The use of statins or ASA is not associated with a lower risk or a milder course of PEP.

Early Weight-Based Aggressive vs. Non-Aggressive Goal-Directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis: An Open-Label Multicenter Randomized Controlled Trial (The WATERFALL Trial), Design, and Rationale.

Treatment options are limited for acute pancreatitis (AP). Early aggressive fluid resuscitation (AFR) has been widely considered beneficial because of theoretical improvement in end-organ perfusion, including the pancreas and gut, with pancreatic necrosis and bacterial translocation as consequences of ischemia. There is scarce direct evidence for its association to improved outcomes. Furthermore, it has been described that AFR may be associated with poor outcomes in severe AP. WATERFALL is an investigator-initiated international multicenter open-label randomized controlled trial comparing AFR vs. moderate fluid resuscitation (MFR) in AP. The main outcome variable will be the incidence of moderate to severe AP (a clinically relevant outcome that has been validated). Aggressive fluid resuscitation will consist in lactated Ringer solution (LR) 20-mL/kg bolus (administered over 2 h) followed by LR 3 mL/kg per hour. Patients randomized to MFR will receive an LR bolus 10 mL/kg in case of hypovolemia or no bolus in patients with normal volemia, followed by LR 1.5 mL/kg per hour. The patients will be assessed at 3 (±1), 12 (±4), 24 (±4), 48 (±4), and 72 (±4) h from recruitment, and fluid resuscitation will be adjusted to the patient's clinical and analytical status according to a protocol. Based on a prospective multicenter study, the incidence of moderate to severe AP is 35%. Sample sizes of 372 patients per group (overall 744) achieve 80% power to detect a difference in the incidence of moderate to severe AP of 10%, at a significance level (α) of 0.05 using a two-sided z-test, assuming a 10% dropout rate. These results assume that three sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries.

Statin consumption and risk of post-endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND: The most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP) is post-ERCP acute pancreatitis (PEP). Statin consumption seems to lower the incidence of acute pancreatitis. We aimed to investigate the relationship between the use of statins and the incidence of PEP. METHODS: multicenter (4 Spanish tertiary-level public hospitals) retrospective cohort study. Adult patients undergoing an ERCP were included in the study. We excluded patients with chronic pancreatitis, with ongoing acute pancreatitis and those who developed other complications after ERCP. Patients were classified into 2 groups: those under statin treatment (group S) and controls (group C). A multivariate analysis was performed (binary logistic regression) including age, center, female gender, previous pancreatitis, suspected sphincter of Oddi dysfunction, difficult cannulation (>10 min), >1 pancreatic guidewire passages, pancreatic injection, pancreatic stenting and presence of choledocholitiasis. RESULTS: seven hundred and two patients were included, median age 74 (62-82 years), 330 (47%) females, 223 (32%) in group S. Thirty-five (5%) patients developed PEP, 6 (3%) in group S and 29 (6%) in group C. Statin use was not associated with a lower frequency of PEP in univariate analysis, OR 0.429 (95% confidence interval 0.176-1.05, p = 0.06) or in multivariate analysis, adjusted OR 0.5 (0.19-1.32), p = 0.16. Statin use had no effect on severity of PEP, being mild in 50% vs 78.6% in non-statin users, p = 0.306. CONCLUSIONS: the chronic use of statins was not associated with a decreased risk of PEP or a milder course of disease in our sample of patients.

Towards evidence-based and personalised care of acute pancreatitis.

Acute pancreatitis is a heterogeneous illness. Most patients experience a mild course of disease, but one third will develop local complications and/or organ failure associated with increased morbidity and risk of mortality. Diagnosis of acute pancreatitis is based on typical epigastric pain, elevation of serum lipase or amylase levels, and/or characteristic findings on imaging. Personalised management is needed in patients with acute pancreatitis. Currently, analgesia, Ringer's lactate solution-based goal-directed fluid resuscitation and early oral refeeding providing enteral nutrition if not tolerated are the cornerstones for early management. Prophylactic antibiotics or endoscopic retrograde cholangiopancreatography in the absence of cholangitis are considered to be futile. Future clinical trials should address optimal fluid resuscitation, the early administration of anti-inflammatory drugs and the exact role of nutritional support in severe acute pancreatitis. Here, we present a patient case and review the diagnosis, treatment and prognosis of acute pancreatitis.

Simvastatin in the Prevention of Recurrent Pancreatitis: Design and Rationale of a Multicenter Triple-Blind Randomized Controlled Trial, the SIMBA Trial.

Background: One in every four patients with a first episode of non-gallstone-related acute pancreatitis (AP) develops recurrent disease. Recurrent episodes of AP or acute flares of chronic pancreatitis (CP) are associated with decreased quality of life and progression of the disease. Besides removing the etiology of pancreatitis (which sometimes is not possible), there are no effective measures to prevent recurrence. Meta-analyses of randomized controlled trials, as well as epidemiological and cohort studies, suggest that statins may be protective against the development of index AP. Methods: The SIMBA study is a triple-blind randomized placebo-controlled, parallel-group multicenter trial. Patients with recurrent AP or with acute flares of CP (at least two episodes in the last 12 months) will be randomized to receive simvastatin 40 mg daily or placebo. During a 3-year study period, 144 patients (72 per arm of treatment) from 26 centers will be enrolled. The patients will receive the study treatment for 1 year. The primary aim is to compare the recurrence of AP or acute flares in CP. Secondary endpoints include the incidence of new-onset diabetes mellitus, new-onset exocrine pancreatic insufficiency (EPI), new-onset imaging signs of CP, frequency of all-cause hospital admissions, severity of AP, adherence to treatment, and frequency of adverse events. Discussion: The SIMBA trial will ascertain whether simvastatin, a safe, widely used and inexpensive drug, can change the natural course of recurrent pancreatitis. Trial Registration: ClinicalTrials.gov Identifier: NCT04021498.

Statin use is not associated with an increased risk of acute pancreatitis-A meta-analysis of observational studies.

BACKGROUND: Statins are perceived as potential etiological factors for acute pancreatitis (AP), but recent evidence suggests the opposite. Our aim was to evaluate the association between statin use and risk of AP in observational studies. METHODS: Medline, Scopus, and Web of Science were searched for cohort (C) and case-control (CC) studies evaluating statins as intervention and AP as outcome. Pooled adjusted odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. RESULTS: Thirteen studies (seven CC, six C) with 34,899 AP patients and 5,377,894 controls were included. Prevalence of statin use was 9.8% among AP patients and 25% among controls. Pooled adjusted OR was 1.00 (95% CI = 0.63 to 1.59) with considerable heterogeneity (I 2 = 98%). CC studies were associated with increased AP risk (OR = 1.33; 95% CI = 1.20 to 1.47), unlike C studies (OR = 0.69; 95% CI = 0.37 to 1.31). No association with increased risk was found for studies from Western countries (OR = 0.90; 95% CI = 0.52 to 1.56), unlike for studies conducted in Asia (OR = 1.39; 95% CI = 1.10 to 1.75). CONCLUSION: Statin use is not associated with increased risk of AP. Increased risk was limited to CC studies, which are more prone to bias, while C studies showed no global effect. Further research is needed to clarify whether statin type, dosage, treatment duration or AP etiology might account for this difference.

Chronic use of statins and risk of post-ERCP acute pancreatitis (STARK): Study protocol for an international multicenter prospective cohort study.

BACKGROUND: Acute pancreatitis (AP) is the most common complication after endoscopic retrograde cholangiopancreatography (ERCP). Statins have been traditionally associated to an increased risk of AP, however, recent evidence suggests that statins may have a protective role against this disease. AIMS: Our primary aim is to investigate whether the use of statins has a protective effect against post-ERCP pancreatitis (PEP). Secondary outcomes are: to evaluate the effect of other drugs on the incidence of PEP; to ascertain the relationship between the use of statins and the severity of PEP; and to evaluate the effect of other risk and protective factors on the incidence of PEP. METHODS: STARK is an international multicenter prospective cohort study. Centers from Spain, Italy, Croatia, Finland and Sweden joined this study. The total sample size will include about 1016 patients, which was based on assuming a 5% incidence of PEP among non-statin (NSt) users, a 1-3 ratio of statin (St) and NSt consumers respectively, a 70% decrease in PEP among St consumers, an alpha-error of 0.05 and beta-error of 0.20. All patients aged ≥18 years scheduled for ERCP will be offered to enter the study. DISCUSSION: STARK study will ascertain whether statins, a safe, widely used and inexpensive drug, can modify the incidence of PEP.

Oleic acid chlorohydrin, a new early biomarker for the prediction of acute pancreatitis severity in humans.

BACKGROUND: The early prediction of the severity of acute pancreatitis still represents a challenge for clinicians. Experimental studies have revealed the generation of specific halogenated lipids, in particular oleic acid chlorohydrin, in the early stages of acute pancreatitis. We hypothesized that the levels of circulating oleic acid chlorohydrin might be a useful early prognostic biomarker in acute pancreatitis in humans. METHODS: In a prospective, multicenter cohort study, plasma samples collected within 24 h after presentation in the emergency room from 59 patients with acute pancreatitis and from 9 healthy subjects were assessed for oleic acid chlorohydrin levels. RESULTS: Pancreatitis was mild in 30 patients, moderately severe in 16 and severe in 13. Oleic acid chlorohydrin levels within 24 h after presentation were significantly higher in patients that later progressed to moderate and severe acute pancreatitis. Using 7.49 nM as the cutoff point, oleic acid chlorohydrin distinguished mild from moderately severe-to-severe pancreatitis with high sensitivity/specificity (96.6/90.0%) and positive/negative predictive values (90.3/96.4%). Using 32.40 nM as the cutoff value sensitivity, specificity, positive and negative predictive values were all 100% for severe acute pancreatitis. It was found to be a better prognostic marker than BISAP score, hematocrit at 48 h, SIRS at admission, persistent SIRS or C-reactive protein at 48 h. CONCLUSIONS: Oleic acid chlorohydrin concentration in plasma is elevated in patients with acute pancreatitis on admission and correlates with a high degree with the final severity of the disease, indicating that it has potential to serve as an early prognostic marker for acute pancreatitis severity.