Cytokines and inflammatory mediators: Markers involved in interstitial damage to the pancreas in two dengue fever cases associated with acute pancreatitis.

Dengue viral (DENV) infections can lead to acute pancreatitis and associated tissue damage. This study examined the pancreas from two fatal cases of DENV for histopathological changes as well as for the detection of cytokines, and other inflammatory mediators. Tissue sections were prepared for examination by ultrastructural and histopathological techniques. Sections from the pancreas of non-infected individuals were prepared in parallel as a control. The presence of viral replication in macrophages was detected by co-staining for the proteins NS3 and CD68 by immunofluorescence. Immunohistochemistry was used to detect cells that expressed cytokines and inflammatory mediators to characterize the inflammatory response. Edema, acinar necrosis and fibrosis areas associated with a mononuclear infiltrate were found in infected tissues. The major site of virus replication appeared to be macrophages based on their exclusive presentation of the viral protein NS3. Pancreatic tissues from the infected individuals also displayed increased levels of high mobility group box-1, caspase-3, gelatinase B and tumor necrosis factor alpha compared to controls. The presence of virus replicating macrophages in the pancreas was associated with multiple changes in tissue structure that included elevated levels of cytokines and inflammatory markers that may differentiate acute pancreatitis due to DENV infections from other causes.

Differential metabolism-associated gene expression of duck pancreatic cells in response to two strains of duck hepatitis A virus type 1.

Several outbreaks of duck hepatitis A virus type 1 (DHAV-1), which were characterized by yellow coloration and hemorrhage in pancreatic tissues, have occurred in China. The causative agent is called pancreatitis-associated DHAV-1. The mechanisms involved in pancreatitis-associated DHAV-1 infection are still unclear. Transcriptome analysis of duck pancreas infected with classical-type DHAV-1 and pancreatitis-associated DHAV-1 was carried out. Deep sequencing with Illumina-Solexa resulted in a total of 53.9 Gb of clean data from the cDNA library of the pancreas, and a total of 29,597 unigenes with an average length of 993.43 bp were generated by de novo sequence assembly. The expression levels of D-3-phosphoglycerate dehydrogenase, phosphoserine aminotransferase, and phosphoserine phosphatase, which are involved in glycine, serine, and threonine metabolism pathways, were significantly downregulated in ducks infected with pancreatitis-associated DHAV-1 compared with those infected with classical-type DHAV-1. These findings provide information regarding differences in expression levels of metabolism-associated genes between ducks infected with pancreatitis-associated DHAV-1 and those infected with classical-type DHAV-1, indicating that intensive metabolism disorders may contribute to the different phenotypes of DHAV-1-infection.

Coxsackievirus B4 sewage-isolate induces pancreatitis after oral infection of mice.

Numerous serotypes which belong to the genus Enterovirus (EV) show variability in their virulence and clinical manifestations. They are also known to undergo changes caused by mutations and recombination during their circulation in the environment and the population. Various EV serotypes are prevalent in groundwater, wastewater and surface waters. Our previous studies showed that oral infection induces pancreatitis depending on specific conditions, such as gravidity, in an outbred murine model. Our aim in the present study was to further explore the pancreatic histopathology in an outbred mouse model following oral infection with clinical isolates from a patient who had aseptic meningitis and an isolate from a treated-sewage sample recovered from the residential area of the patient. The isolates were identified as coxsackievirus B4 (CVB4) in tissue culture. The CVB4 sewage-isolate induced pancreatitis after oral infection. In contrast, pancreatitis was absent following infection with the clinical isolates. Comparison of polyprotein sequences showed that the treated-sewage strains differed from the patient's isolates by 9 and 11 amino acids. We conclude that the isolates of clinical and environmental origin differed in their pathogenic properties and showed genetic variation.

The impact of the COVID-19 epidemic on hospital admissions for alcohol-related liver disease and pancreatitis in Japan.

During the coronavirus disease 2019 (COVID-19) pandemic, there have been health concerns related to alcohol use and misuse. We aimed to examine the population-level change in cases of alcohol-related liver disease and pancreatitis that required admission during the COVID-19 epidemic by interrupted time series (ITS) analysis using claims data. We defined the period from April 2020, when the Japanese government declared a state of emergency, as the beginning of the COVID-19 epidemic. This ITS analysis included 3,026,389 overall admissions and 10,242 admissions for alcohol-related liver disease or pancreatitis from 257 hospitals between July 2018 and June 2020. The rate of admissions per 1000 admissions during the COVID-19 epidemic period (April 2020-June 2020) was 1.2 times (rate ratio: 1.22, 95% confidence interval: 1.12-1.33) compared to the pre-epidemic period. Analyses stratified by sex revealed that the increases in admission rates of alcohol-related liver disease or pancreatitis for females were higher than for males during the COVID-19 epidemic period. The COVID-19 epidemic in Japan might associates an increase in hospital admissions for alcohol-related liver disease and pancreatitis. Our study could support the concern of alcohol consumption and health problems during the COVID-19 pandemic.

Abdominal and gastrointestinal manifestations in COVID-19 patients: Is imaging useful?

Coronavirus disease 2019 (COVID-19) can be considered a systemic disease with a specific tropism for the vascular system, in which the alterations of the microcirculation have an important pathogenetic role. The lungs are the main organ involved in COVID-19, and severe progressive respiratory failure is the leading cause of death in the affected patients; however, many other organs can be involved with variable clinical manifestations. Concerning abdominal manifestations, the gastrointestinal tract and the hepatobiliary system are mainly affected, although the pancreas, urinary tract and spleen may also be involved. The most common gastrointestinal symptoms are loss of appetite, followed by nausea and vomiting, diarrhea and abdominal pain. Gastrointestinal imaging findings include bowel wall thickening, sometimes associated with hyperemia and mesenteric thickening, fluid-filled segments of the large bowel and rarely intestinal pneumatosis and ischemia. Hepatic involvement manifests as an increase in the enzymatic levels of alanine aminotransferase, aspartate aminotransferase, serum bilirubin and γ-glutamyl transferase with clinical manifestations in most cases mild and transient. The most frequent radiological features are hepatic steatosis, biliary sludge and gallstones. Edematous acute pancreatitis, kidney infarct and acute kidney injury from acute tubular necrosis have been described more rarely in COVID-19. Lastly, splenic involvement is characterized by splenomegaly and by the development of solitary or multifocal splenic infarcts with classic wedge-shaped or even rounded morphology, with irregular or smooth profiles. In summary, the abdominal radiological findings of COVID-19 are nonspecific and with poor pathological correlation reported in the literature. Ultrasound and particularly computed tomography with multiphasic acquisition are the diagnostic methods mainly utilized in COVID-19 patients with abdominal clinical symptoms and signs. Although radiological signs are not specific of abdominal and gastrointestinal involvement, the diagnostic imaging modalities and in particular computed tomography are helpful for the clinician in the management, evaluation of the severity and evolution of the COVID-19 patients.

Pancreatic damage in COVID-19: Why? How?

OBJECT: We aimed to evaluate the elevation of amylase and lipase enzymes in coronavirus disease 2019 (COVID-19) patients and their relationship with the severity of COVID-19. METHOD: In this study, 1378 patients with COVID-19 infection were included. Relation of elevated amylase and lipase levels and comorbidities with the severity of COVID-19 was analysed. The effects of haemodynamic parameters and organ failure on pancreatic enzymes and their relations with prognosis were statistically analysed. RESULTS: The 1378 patients comprised of 700 (51.8%) men and 678 (%49.2) women. Of all patients, 687 (49.9%) had mild and 691 (50.1%) patients had severe COVID-19 infection. Amylase elevation at different levels occurred in 316 (%23) out of 1378 patients. In these patients, the amylase levels increased one to three times in 261 and three times in 55 patients. Pancreatitis was detected in only six (%1.89) of these patients according to the Atlanta criteria. According to univariate and multivariate analyses, elevated amylase levels were significantly associated with the severity of COVID-19 (odds ratio [OR]: 4.37; P < .001). Moreover, diabetes mellitus (DM; OR: 1.82; P = .001), kidney failure (OR: 5.18; P < .001), liver damage (OR: 6.63; P < .001), hypotension (OR: 6.86; P < .001) and sepsis (OR: 6.20; P = .008) were found to be associated with mortality from COVID-19. CONCLUSION: Elevated pancreatic enzyme levels in COVID-19 infections are related to the severity of COVID-19 infection and haemodynamic instability. In a similar way to other organs, the pancreas can be affected by severe COVID-19 infection.

Attenuated strain of CVB3 with a mutation in the CAR-interacting region protects against both myocarditis and pancreatitis.

Coxsackievirus B3 (CVB3), is commonly implicated in myocarditis, which can lead to dilated cardiomyopathy, in addition to causing acute pancreatitis and meningitis. Yet, no vaccines are currently available to prevent this infection. Here, we describe the derivation of a live attenuated vaccine virus, termed mutant (Mt) 10, encoding a single amino acid substitution H790A within the viral protein 1, that prevents CVB3 infection in mice and protects from both myocarditis and pancreatitis in challenge studies. We noted that animals vaccinated with Mt 10 developed virus-neutralizing antibodies, predominantly containing IgG2a and IgG2b, and to a lesser extent IgG3 and IgG1. Furthermore, by using major histocompatibility complex class II dextramers and tetramers, we demonstrated that Mt 10 induces antigen-specific T cell responses that preferentially produce interferon-γ. Finally, neither vaccine recipients nor those challenged with the wild-type virus revealed evidence of autoimmunity or cardiac injury as determined by T cell response to cardiac myosin and measurement of circulating cardiac troponin I levels, respectively. Together, our data suggest that Mt 10 is a vaccine candidate that prevents CVB3 infection through the induction of neutralizing antibodies and antigen-specific T cell responses, the two critical components needed for complete protection against virus infections in vaccine studies.

Newcastle Disease Virus Induced Pathologies Severely Affect the Exocrine and Endocrine Functions of the Pancreas in Chickens.

Newcastle disease virus (NDV) causes a highly contagious and devastating disease in poultry. ND causes heavy economic losses to the global poultry industry by decreasing the growth rate, decrease in egg production high morbidity and mortality. Although significant advances have been made in the vaccine development, outbreaks are reported in vaccinated birds. In this study, we report the damage caused by NDV infection in the pancreatic tissues of vaccinated and specific-pathogen-free chickens. The histopathological examination of the pancreas showed severe damage in the form of partial depletion of zymogen granules, acinar cell vacuolization, necrosis, apoptosis, congestion in the large and small vessels, sloughing of epithelial cells of the pancreatic duct, and mild perivascular edema. Increased plasma levels of corticosterone and somatostatin were observed in NDV-infected chicken at three- and five- days post infection (DPI). A slight decrease in the plasma concentrations of insulin was noticed at 5 DPI. Significant changes were not observed in the plasma levels of glucagon. Furthermore, NDV infection decreased the activity and mRNA expression of amylase, lipase, and trypsin from the pancreas. Taken together, our findings highlight that NDV induces extensive tissue damage in the pancreas, decreases the activity and expression of pancreatic enzymes, and increases plasma corticosterone and somatostatin. These findings provide new insights that a defective pancreas may be one of the reasons for decreased growth performance after NDV infection in chickens.

Primary varicella-zoster virus infection of the immunocompromised associated with acute pancreatitis and hemophagocytic lymphohistiocytosis: A case report.

RATIONALE: Primary varicella-zoster virus (VZV) infection may be associated with hemophagocytic lymphohistiocytosis (HLH), as well as with acute pancreatitis. However, there is few data concerning the evolution and the optimal treatment of these rare associations. PATIENT CONCERNS: A 57-year-old immunocompromised woman, who was treated for chronic lymphocytic leukemia 3 years prior to admission, was hospitalized with abdominal pain revealing severe acute pancreatitis. The day after admission, a pruritic rash appeared on her face, trunk, and limbs, sparing the palmoplantar regions. At the same time, fever, thrombocytopenia (27 × 109/L), major hyperferritinemia (11,063 µg/mL), hypertriglyceridemia (2.56 mmol/L) and elevated lactate dehydrogenase levels (1441 IU/L) suggested HLH. DIAGNOSIS: The diagnosis of chickenpox (varicella) was established. Primary VZV infection was then confirmed: cutaneous and plasma VZV polymerase chain reactions were positives, VZV serology was negative for IgG. INTERVENTIONS: Treatment with aciclovir was started intravenously after the onset of the rash, for a total of 10 days. A 48-h surveillance in intensive care was carried out. OUTCOMES: Acute pancreatitis and biological abnormalities evolved favorably under aciclovir. Platelet count was normalized 6 days after admission to hospital. LESSONS: A favorable outcome of primary VZV infection associated with severe acute pancreatitis and probable HLH in an immunocompromised patient is possible with aciclovir alone.

Acute pancreatitis in a patient with COVID-19.

COVID-19 mainly causes pulmonary disease. Involvement of gastrointestinal and hepatobiliary systems, among other systems, has been reported. We report a case of acute pancreatitis in a patient with resolving COVID-19 pneumonia. History taking and investigations excluded other causes of pancreatitis. This case demonstrates the possibility of pancreatic injury in patients with COVID-19, in line with previously reported similar cases. We believe that it is imperative to screen patients presenting with acute pancreatitis for SARS-CoV-2. It is also important to take into consideration that patients with a complicated course who require an invasive procedure such as drainage might pose a risk of transmission to the operating surgeon or interventionist.

CVB3 VP1 interacts with MAT1 to inhibit cell proliferation by interfering with Cdk-activating kinase complex activity in CVB3-induced acute pancreatitis.

Coxsackievirus B3 (CVB3) belongs to the genus Enterovirus of the family Picornaviridae and can cause acute acinar pancreatitis in adults. However, the molecular mechanisms of pathogenesis underlying CVB3-induced acute pancreatitis have remained unclear. In this study, we discovered that CVB3 capsid protein VP1 inhibited pancreatic cell proliferation and exerted strong cytopathic effects on HPAC cells. Through yeast two-hybrid, co-immunoprecipitation, and confocal microscopy, we show that Menage a trois 1 (MAT1), a subunit of the Cdk-Activating Kinase (CAK) complex involved in cell proliferation and transcription, is a novel interaction protein with CVB3 VP1. Moreover, CVB3 VP1 inhibited MAT1 accumulation and localization, thus interfering with its interaction with CDK7. Furthermore, CVB3 VP1 could suppress CAK complex enzymic phosphorylation activity towards RNA Pol II and CDK4/6, direct substrates of CAK. VP1 also suppresses phosphorylation of retinoblastoma protein (pRb), an indirect CAK substrate, especially at phospho-pRb Ser780 and phospho-pRb Ser807/811 residues, which are associated with cell proliferation. Finally, we present evidence using deletion mutants that the C-terminal domain (VP1-D8, 768-859aa) is the minimal VP1 region required for its interaction with MAT1, and furthermore, VP1-D8 alone was sufficient to arrest cells in G1/S phase as observed during CVB3 infection. Taken together, we demonstrate that CVB3 VP1 can inhibit CAK complex assembly and activity through direct interaction with MAT1, to block MAT1-mediated CAK-CDK4/6-Rb signaling, and ultimately suppress cell proliferation in pancreatic cells. These findings substantially extend our basic understanding of CVB3-mediated pancreatitis, providing strong candidates for strategic therapeutic targeting.

Model systems for studying extrahepatic pathogenesis of hepatitis E virus. Current knowledge and future directions.

Hepatitis E Virus is the most common cause of acute viral hepatitis globally. HEV infection is endemic in developing countries. Also, autochthonous and sporadic cases are reported in developed countries. HEV causes acute and chronic infections. Besides, extrahepatic manifestations including neurological, renal, haematological, acute pancreatitis and complications during pregnancy are associated with HEV infections. The pathogenesis of HEV in the extrahepatic tissues is either due to direct cytopathic effect mediated by the virus replication, or immunological mechanisms caused by an uncontrollable host response. Researchers have used different in vivo and in vitro models to study the pathogenesis of HEV in the extrahepatic tissues and analyse the host immune response against HEV infection. This review highlights the extrahepatic disorders associated with HEV infection. We focused on the in vivo and in vitro models as a tool for elucidating the HEV infection beyond the liver and studying the mechanisms of HEV induced tissue damages.

A food-responsive switch modulates TFEB and autophagy, and determines susceptibility to coxsackievirus infection and pancreatitis.

Almost a billion people worldwide are chronically undernourished. Herein, using a mouse model of coxsackievirus B3 (CVB3) infection, we report that a single day of food restriction (FR) markedly increases susceptibility to attenuated enterovirus infection, replication, and disease. These "pro-viral" effects, which are rapidly-reversed by the restoration of food, are mediated by several genes whose expression is altered by FR, and which support CVB3 replication. Central to this is TFEB, a protein whose expression and activation status are rapidly increased by FR. TFEB, which regulates the transcription of >100 genes involved in macroautophagy/autophagy and lysosomal biogenesis, responds similarly to both FR and CVB3 infection and plays a pivotal role in determining host susceptibility to CVB3. We propose that, by upregulating TFEB, FR generates an intracellular environment that is more hospitable to the incoming virus, facilitating its replication. This interplay between nutritional status and enterovirus replication has implications for human health and, perhaps, for the evolution of these viruses.Abbreviations: Atg/ATG: autophagy-related; CAR: Coxsackievirus and adenovirus receptor; Cas9: CRISPR associated protein 9; Cre: recombinase that causes recombination; CRISPR: clustered regularly interspaced short palindromic repeats; Ctsb/CTSB: cathepsin B; CVB3: coxsackievirus B3; DsRedCVB3: a recombinant CVB3 that encodes the Discosoma red fluorescent protein; EL: elastase; FR: food restriction; GFP: green fluorescent protein; gRNA: guide RNA; HBSS: Hanks Buffered Salt Solution; LYNUS: lysosomal nutrient sensing machinery; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; Nluc: nanoluciferase; NlucCVB3: a recombinant CVB3 encoding nanoluciferase; pfu: plaque-forming unit(s); p.i.: post infection; rCVB: recombinant coxsackievirus B3; RPS6KB/p70S6K: ribosomal protein S6 kinase; RT: room temperature; siRNA: small interfering RNA; TFEB: transcription factor EB; tg: transgenic; TUBB: ß-tubulin; UNINF: uninfected; wrt: with respect to; WT: wild type.

A case-control emergency department-based analysis of acute pancreatitis in Covid-19: Results of the UMC-19-S6.

BACKGROUND/PURPOSE: We investigated the incidence, risk factors, clinical characteristics and outcomes of acute pancreatitis (AP) in patients with COVID-19 attending the emergency department (ED), before hospitalization. METHODS: We retrospectively reviewed all COVID patients diagnosed with AP in 62 Spanish EDs (20% of Spanish EDs, COVID-AP) during the COVID outbreak. We formed two control groups: COVID patients without AP (COVID-non-AP) and non-COVID patients with AP (non-COVID-AP). Unadjusted comparisons between cases and controls were performed regarding 59 baseline and clinical characteristics and four outcomes. RESULTS: We identified 54 AP in 74 814 patients with COVID-19 attending the ED (frequency = 0.72‰, 95% CI = 0.54-0.94‰). This frequency was lower than in non-COVID patients (2231/1 388 879, 1.61‰, 95% CI = 1.54-1.67; OR = 0.44, 95% CI = 0.34-0.58). Etiology of AP was similar in both groups, being biliary origin in about 50%. Twenty-six clinical characteristics of COVID patients were associated with a higher risk of developing AP: abdominal pain (OR = 59.4, 95% CI = 23.7-149), raised blood amylase (OR = 31.8; 95% CI = 1.60-632) and vomiting (OR = 15.8, 95% CI = 6.69-37.2) being the strongest, and some inflammatory markers (C-reactive protein, procalcitonin, platelets, D-dimer) were more increased. Compared to non-COVID-AP, COVID-AP patients differed in 23 variables; the strongest ones related to COVID symptoms, but less abdominal pain was reported, pancreatic enzymes raise was lower, and severity (estimated by BISAP and SOFA score at ED arrival) was higher. The in-hospital mortality (adjusted for age and sex) of COVID-AP did not differ from COVID-non-AP (OR = 1.12, 95% CI = 0.45-245) but was higher than non-COVID-AP (OR = 2.46, 95% CI = 1.35-4.48). CONCLUSIONS: Acute pancreatitis as presenting form of COVID-19 in the ED is unusual (<1‰ cases). Some clinically distinctive characteristics are present compared to the remaining COVID patients and can help to identify this unusual manifestation. In-hospital mortality of COVID-AP does not differ from COVID-non-AP but is higher than non-COVID-AP, and the higher severity of AP in COVID patients could partially contribute to this increment.

Viral-Attributed Acute Pancreatitis: A Systematic Review.

Infectious etiologies are rare cause of acute pancreatitis (AP). We sought to investigate the frequency of viral-attributed AP (VIAP) and describe its natural course and clinical features. Comprehensive review of PubMed and EMBASE in English until December 31, 2019, was performed. AP diagnosis and severity were defined per the Revised Atlanta Classification. Viral infections were diagnosed by serology and/or histology. A diagnosis of viral infection, with a concurrent AP diagnosis, a temporal resolution of both entities, and the attempt to exclude the most common etiologies of AP defined VIAP. Two independent reviewers reviewed eligible publications. Bias risk was assessed with the Murad tool. A total of 209 cases identified in 128 publications met inclusion criteria. Mean age was 38.9 ± 1.28 years. Male-to-female ratio was 2.2:1, and 28% of patients were immunocompromised. Viral hepatitis (A, B, C, D and E) was the most common virus and accounted for 34.4% of cases, followed by coxsackie and echoviruses (14.8%), hemorrhagic fever viruses (12.4%), CMV (12.0%), VZV (10.5%), mumps and measles (3.8%), primary HIV infection (3.8%), HSV (1.9%), EBV (1.9%), and the remainder of cases (2.9%) attributed to adenovirus, influenza H1N1, and multiple viruses. Severity of AP was: 43.1% mild, 11.7% moderately severe, 32.4% severe. Death occurred in 42 (20.1%) patients. A significant portion of VIAP patients were immunocompromised (28.0%) and accounted for 71.4% of mortality cases. Mortality was higher than that reported for AP from other etiologies in the literature.

Involvement of the exocrine pancreas during COVID-19 infection and possible pathogenetic hypothesis: a concise review.

The gastrointestinal system may be affected by COVID-19 infection with an incidence variable from 3% up to 79%. Several works show that the pancreas, both in its exocrine and endocrine function, can be affected by this viral infection, although this organ has been poorly analyzed in this current epidemic context. This mini-review aims to provide a summary of available studies on exocrine pancreas involvement during COVID-19 infection. A search through MEDLINE/PubMed was conducted on the topic in hand. With regard to exocrine function, some studies highlight the presence of an associated hyperenzymemia (hyperamylasemia, hyperlipasemia), while others describe isolated and rare cases of acute pancreatitis. More attention should be paid to pancreatic impairment in subjects with COVID-19, as this may prove to be one of the elements aggravating its clinical course. Indeed, acute pancreatitis, especially when presenting in severe forms with hyperstimulation of the pro-inflammatory response, may represent a crucial factor in the progression of COVID-19, entailing both an increase in hospitalization days and in mortality rate.

Insufficient etiological workup of COVID-19-associated acute pancreatitis: A systematic review.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, mostly causing respiratory symptoms, is also known to affect the gastrointestinal tract. Several case reports hypothesize that SARS-CoV-2 could be an etiological factor in acute pancreatitis (AP). AIM: To assess all the available evidence in the literature relating to coronavirus disease 2019 (COVID-19) and AP. METHODS: We performed a systematic review of the available literature on the topic. The systematic search was conducted on 15 May 2020 on MEDLINE, EMBASE, CENTRAL, Web of Science and Scopus with a search key using the terms "amylase," "lipase," "pancr*," "COVID-19" and synonyms. Due to the low quality and poor comparability of the studies, a meta-analysis was not performed. RESULTS: Six case reports and two retrospective cohorts were included, containing data on eleven COVID-19 patients with AP. Five patients had AP according to the Atlanta classification. Other publications did not provide sufficient information on the diagnostic criteria. Most cases were considered SARS-CoV-2-induced, while several established etiological factors were not investigated. We were able to identify other possible causes in most of them. CONCLUSION: We strongly highlight the need for adherence to the guidelines during a diagnostic and etiological workup, which could alter therapy.