Clinical Case Summary

Renal transplant recipients are at an increased risk of opportunistic infections, and a subset of this population may develop de novo inflammatory bowel disease (IBD). Differentiating the various forms of post-transplant colitis is challenging. Chronic active EBV enteritis is rarely reported and easily misdiagnosed as IBD, which results in death in severe cases.
A 61-year-old man with a history of kidney transplant presented with bloody diarrhea, fever and weight loss. Ileocolonoscopy showed ulcers in the ileum and the right colon. He was empirically started on ganciclovir and mycophenolate mofetil (MMF) was suspended. Colonic biopsies showed unspecific findings. Cytomegalovirus infection, Clostridioides difficile infection, intestinal tuberculosis and lymphoproliferative disease were excluded. The hypothesis of de novo IBD was postulated. Two months later the patient presented with non-bloody diarrhea and fever. Steroid therapy was increased and everolimus was added. A repeat ileocolonoscopy showed pancolitis and ileitis with oval transversal ulcers. Biopsies were positive for EBV by in-situ hybridization, suggesting an EBV-induced enteritis. Serum viral load was 1397 IU/mL. Immunosuppression was reduced and intravenous immunoglobulin therapy was administered. The patient did not respond and developed hemorrhagic shock with indication for salvage surgery (subtotal colectomy). Less than one month later the patient died due to hemorrhagic shock.
Chronic active EBV infective enteritis should be considered for patients who exhibit IBD-like symptoms and showing irregular ulcers in both colon and small intestine. Clinicians should recognize the presence of EBV infection to avoid misdiagnosis. However, chronic immunosuppression and opportunistic infections, such as EBV, are potential triggers of de novo IBD. Management is challenging and still controversial. Janus kinase inhibitors represent a promising treatment strategy as they target the EBV-driven pathway.

References

- Choi C, Yu Q, Deb PQ, Wang W. Rare case of EBV-induced colitis in an immunocompetent individual. BMJ Open Gastroenterol. 2020;7(1):e000360;
- Liu R, Wang M, Zhang L, et al. The clinicopathologic features of chronic active Epstein-Barr virus infective enteritis. Mod Pathol. 2019;32(3):387-395;
- Gioco R, Puzzo L, Patanè M, et al. Post-transplant colitis after kidney transplantation: clinical, endoscopic and histological features. Aging (Albany NY). 2020;12(24):24709-24720;
- Zhang H, Zhao S, Cao Z. Impact of Epstein-Barr virus infection in patients with inflammatory bowel disease. Front Immunol. 2022;13:1001055;
- Lv K, Yin T, Yu M, Chen Z, Zhou Y, Li F. Treatment Advances in EBV Related Lymphoproliferative Diseases. Front Oncol. 2022;12:838817.

Introduction

Gastric injury induces metaplasia is based on parietal cells loss and reprogramming chief cells into proliferative, mucin-rich spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Previously, we demonstrated that parietal cell-selective Slc26a9 deficiency in mice promotes the development of SPEM and progress to gastric intraepithelial neoplasia in mice (Liu et al., Cellular oncology; 2022; Deng et al., DDW2023). However, the exact role of Slc26a9 in injury-induced metaplasia is need further investigated.

Aims & Methods

We used immunostaining to characterize the expression pattern of Slc26a9 during murine gastric development, homeostasis, and injury in homeostasis, after conditionial genetic deletion of Slc26a9. Furthermore, to reveal the functional role of Slc26a9, Injury-induced metaplasia was established in Slc26a9^fl/fl mice and Slc26a9^fl/fl/Atp4b-Cre mice with high-dose tamoxifen.

Results

Mice with parietal cell selective Slc26a9 deficiency first developed spontaneous parietal cell damage, which subsequently led to SPEM. Parietal cell injury was associated with the release of typical pyroptosis factors, including NRLP3, Caspase-1, ASC, GasderminD, IL-1β and IL-18. At the same time, SLC26A9 colocalized with caspase1, NLRP3, GSDMD, and NLRP3 and GSDMD, and produced a large number of reactive oxygen species (ROS), markers of mitochondrial damage, thereby expanding membrane perforation of GSDMD-N fragments and amplifying inflammasome-mediated parietic cell pyrodeath. At the same time, electron microscopy showed that after the knockout of the Slc26a9 gene, the mitochondria of the murine wall cells were obviously swollen, the cell membrane structure was blurred and damaged, the matrix was more dissolved, the ridge was broken and disappeared, and there were many bubble protrusions. This suggests that parietal cell specific SLC26A9 gene deletion may lead to parietal cell scorch death through mitochondrial damage mediated by GSDMD. However, with a large number of parietal cell damage and loss, gastric hypergastrinemia stimulates Tuft cell proliferation and migration to the gastric mucosa for colonization, and secretes a series of alarm hormones such as IL-25, IL-33, HMGB1. Moreover, ILC2 cell secretory factors such as IL-17RA and IL-17RB, GATA3, CD90, CD25 were up-regulated. M2 macrophage polarization-related markers such as Arg1, Fizz1, Ym1, Klf4 and secreted chemokines such as CCL24 and CCL22 were significantly up-regulated. The immunofluorescence staining of F4/80+ and CD163+ was significantly increased. This suggests that the spontaneous injury of parietal cells caused by the deletion of SLC26A9 gene in gastric parietal cells may lead to gastric dysfunction (hypoacid and hypergastrinemia) and mucosal epithelial injury, which may promote the occurrence of SPEM through IL-25 mediating the activation of ILC2 cells to regulate the cellular immune mechanism of macrophage M2 polarization.

Conclusion

Slc26a9 target deletion in parietal cells leads to spontaneous damage and scorch death of parietal cells, which is the core target and cell origin of initiating SPEM. After parietal cell specific Slc26a9 gene deletion leads to spontaneous injury of parietal cells, gastric dysfunction and mucosal injury result in the release of alarm hormone IL-25, which promotes the development of SPEM by activating IL-25-ILC2-macrophage M2 polarization axis. Slc26a9 plays an important protective role in stabilizing gastric epithelial cell differentiation and gastric mucosal immune homeostasis.

Disclosure

No conflict of interest

Introduction

Etiology of acute pancreatitis can be established in the majority of patients. However, in 25 % of cases it remains elusive. Biliary microlithiasis/sludge is detected in up to 75% of patients with idiopathic acute pancreatitis (IAP). As recurrent biliary pancreatitis can be prevented, the underlying etiology of IAP should be established. The aim of this multicentre retrospective study was to develop a machine learning-aided non-invasive prediction tool to guide clinicians in the selection of idiopathic acute pancreatitis patients to be referred to endosonography to establish etiology and allow treatment.

Aims & Methods

We retrospectively used routinely recorded clinical and laboratory parameters of 218 consecutive patients with confirmed acute pancreatitis admitted to our tertiary care hospital between 2015 and 2020. Patients who did not receive endosonography as part of the diagnostic work-up and whose pancreatitis episode could be adequately explained by other causes than biliary sludge and microlithiasis were excluded. We trained supervised machine learning classifiers using H2O.ai automatically selecting the best suitable predictor model to predict microlithiasis/sludge. The predictor model was validated in two independent retrospective cohorts from two tertiary care centers (TU Munich & University Medical Center Göttingen).

Results

28 categorized patients’ variables recorded at admission were identified to compute the predictor model with an accuracy of 0.84 [95% CI 0.791, 0.9185], positive predictive value of 0.84 and negative predictive value 0.80 in the identification cohort (218 patients). In the validation cohort, the robustness of the prediction model was confirmed with an accuracy of 0.76 [95% CI 0.673, 0.8347], positive predictive value of 0.76 and negative predictive value of 0.78 (117 patients).

Conclusion

We present a robust and validated machine learning-based predictor model consisting of routinely recorded lab work at admission that can predict biliary sludge and microlithiasis as cause of acute pancreatitis and select patients for EUS.

Introduction

Autoimmune pancreatitis (AIP) is a rare disease that can be diagnosed, according to the International Consensus Diagnostic Criteria (ICDC). Contrast-enhanced MRI with MRCP has now largely replaced other imaging techniques and ERCP for the assessment of ductal morphology in AIP. A number of MRI-criteria have been proposed, but due to the rarity of the disease the diagnostic imaging criteria have not yet been systematically validated. Aim of the study is to review and optimize the MR-morphologic diagnostic criteria for AIP in terms of specificity and sensitivity in the diagnosis and differential diagnosis of the pancreaticobiliary system.

Aims & Methods

We analyzed retrospectively hundred-fiftysix (n=156) high-quality MRIs: AIP n=56, chronic pancreatitis (CP) n=25, pancreatic cancer (PDAC) n=25, primary sclerosing cholangitis (PSC) n=25, Non-HPB subjects n=25. The MRI reading was conducted in a blinded fashion, using defined criteria by at least two radiological experts. The statistical analysis was performed by means of Proportion test, Chi-square test or Fisher’s exact test, One-way ANOVA and Cohen’s Kappa Statistic of the level of agreement.

Results

The level of agreement between two readers was moderate to substantial agreement (κ 0.23-0.85). Sausage-like enlargment (Reader 1: Sens 30.91%, Spec 98.98%, NPV 71.85%, accuracy 74.51%; Reader 2: Sens 26.79%, Spec 98.00%, NPV 70.50%, accuracy 72.43%), restricted diffusion (Reader 1: Sens 47.83%, Spec 89.29%, NPV 75.76%, accuracy 74.51%; Reader 2: Sens 56.86%, Spec 73.26%, NPV 74.12%, accuracy 72.30%), delayed enhancement in the venous phase (Reader 1: Sens 8.70%, Spec 83.15%, NPV 63.79%, accuracy 74.10%; Reader 2: Sens 32.61%, Spec 79.31%, NPV 69.00%, accuracy 75.19%), the icicle sign (Reader 1: Sens 10.91%, Spec 100%, NPV 66.67%, accuracy 65.30%; Reader 2: Sens 37.50%, Spec 91.00%, NPV 72.22%, accuracy 71.79%) and hyperenhancement of ductal wall (Reader 1: Sens 14.29%, Spec 96.67%, NPV 67.44%, accuracy 71.90%; Reader 2: Sens 8.51%, Spec 95.45%, NPV 66.14%, accuracy 74.10%) show a good accuracy distinguishing AIP from controls. Apparent diffusion coefficient (ADC) was significantly different between AIP, PDAC and CP (ANOVA). The area under the receiver operating characteristic curve (AUROC) was 0.85 (CI 0.73 – 0.97) and 0.68 (CI 0.51 – 0.85) respectively for CP and PDAC.

Conclusion

Our study showed that the Sausage-like enlargment, restricted diffusion, delayed enhancement in the venous phase, the icicle sign and hyperenhancement of ductal wall show a good accuracy distinguishing AIP from controls.

Introduction

Pain in acute pancreatitis is the symptom to be treated urgently. There are currently no recommendations for analgesic management. Intravenous lidocaine has both analgesic and anti-inflammatory effects. Its use has never been evaluated for analgesia in acute pancreatitis. The aim of our study was therefore to evaluate the efficacy and safety of intravenous lidocaine in the management of acute pancreatitis resistant to level I and II analgesics.

Aims & Methods

We conducted a retrospective, monocentric study between January 2015 and December 2021. Patients visiting the emergency department for proven acute pancreatitis and presenting with pain resistant to group I and II analgesics, hospitalized in the hepato-gastroenterology department and treated with intravenous lidocaine, were included. Pain was assessed by retrospective collection of numerical pain scales (NPS) at the emergency department, and at each analgesic re-evaluation. Treatment efficacy was defined as the absence of need for a Level III analgesic (opioids).

Results

154 patients, hospitalized in our gastroenterology unit for acute pancreatitis and presenting with pain refractory to level I and II analgesics treated with intravenous lidocaine were included. Patients were predominantly male, with a median age of 48.5 years [37.0; 58.0]. The main etiology of acute pancreatitis was ethylic in 36% of cases. Acute necrotizing pancreatitis was present in 69% of patients. 44/154 patients received a bolus of opioid morphine in the emergency department before the administration of lidocaine. Lidocaine was prescribed in a continuous way at the dose of 2g/24h (intravenous administration with electric syringe). The median NPS before prescription of lidocaine was 8.0 [7.00; 9.00]. Lidocaine treatment was effective in 88.7% of patients (136/154). 1.3% of patients experienced lidocaine-related adverse events such as skin rash and dysgeusia. In univariate analysis, patients requiring intensive care or developing an acute respiratory distress syndrome were significantly more likely to fail lidocaine (respectively OR = 5.83; CI [1.69; 20.06]; p=0.01 and OR = 4.23; CI [1.44; 12.43]; p=0.009).

Conclusion

Intravenous lidocaine administration appears to be effective and safe for pain control in 89% of patients failing to level I and II analgesia. Further prospective studies are needed to confirm these results.
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