Epstein-Barr virus-associated acute pancreatitis: a clinical report and review of literature.

Epstein-Barr virus (EBV) infection is a common viral infection, especially in children; it could have an asymptomatic course or may present as flu syndrome characterized by fever, malaise, headache, lymphadenitis, and pharyngitis [ 1 ]. EBV infection usually causes an acute self-limiting disease and resolves spontaneously in a few weeks; however, it may be responsible for various complications of the respiratory, cardiovascular, genitourinary, gastrointestinal, and nervous systems, ranging from minor to severe to life threatening. EBV also plays a significant role in the pathogenesis of autoimmune diseases and neoplasms [ 2 ]. As regards gastrointestinal manifestations, enlarged spleen and liver, with elevated transaminase levels, are the most common symptoms. Acute pancreatitis is a disorder of reversible inflammation of the pancreas. Only a few cases are related to infections and the most common pathogens are the viruses responsible for mumps, parotitis, and influenza. EBV-associated acute pancreatitis is a rare condition and it may occur in children and adults. Here we report on a 3-year-old girl with acute pancreatitis due to EBV infection; a review about this topic was also conducted thereafter. A 3-year-old female, previously in good health, was admitted to the “G. Di Cristina” Children's Hospital in Palermo for vomiting and abdominal pain. She did not complain of any other symptoms. Vital signs were normal. On physical examination, she appeared sick, with moderate epigastric tenderness. Laboratory investigations showed hemoglobin 13.8 g/dl, platelet 340,000/mm 3 , white blood cell count 16,600/mm 3 (neutrophils 20%, monocytes 11%, and lymphocytes 69%), C-reactive protein 13,1 mg/dl (normal range < 0.5 mg/dl), aspartate aminotransferase 40 U/l, alanine aminotransferase 25 U/l, total bilirubin 0,11 mg/dl, amylase 913 U/l (normal range 30–100 U/l), and lipase 6450 U/l (normal range 3–32 U/l). Because of fair general conditions and elevated inflammatory markers, empirical antibiotic therapy with cefotaxime was started. Abdominal ultrasound revealed an enlarged pancreas, with hypoechogenic areas; no biliary lithiasis was observed. She had no past history of abdominal trauma, surgery or cholecystitis and any familial history of pancreatitis or gallstones was reported. She did not receive any medications known to cause pancreatitis. Serological tests for mumps, parotitis, rubella, EBV, cytomegalovirus, varicella-zoster virus, herpes simplex virus, coxsackie virus, and mycoplasma were all negative, except for the presence of EBV VCA IgM and IgG (EBNA IgG negative). Exudative pharyngotonsillitis, cervical lymphadenopathy, and hepatosplenomegaly were not present. A diagnosis of EBV-associated acute pancreatitis was made; the patient was treated conservatively, including fasting for three days until the resolution of vomiting, peripheral parenteral nutrition support for seven days, and pain management with acetaminophen. An abdominal ultrasound, performed after five days, did not show any complications and antibiotic therapy was discontinued. She improved clinically, lipase and amylase levels progressively decreased, and enteral feeding was gradually resumed. She was discharged home on the fifteen day of hospitalization.

Acute pancreatitis is an inflammatory disorder of the pancreas; the incidence rate is 3–13 cases per 100,000 per year in the pediatric population [ 3 , 4 ], and 5–60 cases per 100,000 persons per year in adulthood [ 5 ]. According to the American College of Gastroenterology guidelines, the diagnosis of acute pancreatitis is established by the presence of 2 of the 3 following criteria: (i) abdominal pain consistent with the disease, (ii) serum amylase and/or lipase greater than three times the upper limit of normal, and/or (iii) characteristic findings from abdominal imaging [ 6 ]. The most common etiology of acute pancreatitis is gallstones or microlithiasis; other causes include alcohol misuse, trauma, metabolic disorders (hypertriglyceridemia, hypercalcemia), infections (parotitis, mumps, influenza, herpes viruses, hepatitis viruses, coxsackie viruses, mycoplasma), systemic disease (hemolytic uremic syndrome, systemic lupus erythematosus, Henoch-Schönlein purpura, Kawasaki disease, inflammatory bowel diseases), and autoimmune pancreatitis [ 5 , 7 ]. EBV infection is a rare cause of acute pancreatitis; the pathophysiology remains unclear: both direct viral infection and inflammatory process induced by the virus are plausible pathogenic mechanisms [ 8 , 9 ]. A review of the English literature was performed: a PubMed search, using as keywords acute pancreatitis AND (EBV OR Epstein-Barr virus), revealed only 10 pediatric [ 8 , 10 – 18 ] and 6 adult cases [ 9 , 19 – 23 ]. As regards pediatric reports (Table I ), median age and mean age was 12 and 11.8 years respectively (range 3–18), 36% were male and 64% were female. As regards pancreatitis symptoms, abdominal pain was described in all cases, vomiting in 55%, and nausea in 27%; eight patients (73%) also had mononucleosis symptoms, like fever, lymphadenitis, and pharyngitis. Amylase and/or lipase levels were increased up to three times the normal limit in 100% of the cases. In 5 children, there was evidence of acute pancreatitis on abdominal computerized tomography (CT), while only in our case, ultrasound (US) revealed an enlarged pancreas with a heterogeneous echotexture. The diagnosis of pancreatitis was confirmed in all patients, using the diagnostic criteria of the American College of Gastroenterology. Six children presented other complications related to EBV infection: the most common was cholestatic hepatitis (50%); cholecystitis, pneumonia, proctitis, portal vein thrombosis, and septic shock were also reported. Serological documentation for EBV infection was obtained in 10 cases, while in 1 child, the diagnosis was made clinically. All cases were treated with supportive care, that were fasting, intravenous fluids, parenteral nutrition, and/or pain management; in 1 patient, antibiotics and antivirals (meropenem, teicoplanin, and ganciclovir) were also used [ 17 ]. All children recovered. Table I Clinical data of pediatric cases with EBV-associated acute pancreatitis reported in literature and our case Reference Age/sex Mononucleosis symptoms Gastrointestinal symptoms EBV diagnosis Amylase-lipase Imaging Other complications Therapy Outcome Wislocki et al. 1966 [ 10 ] 18y/M Yes Abdominal pain, vomiting Heterophil antibody 480 U/l-NA NA No Fasting, intravenous fluids, analgesics Recovered Hedstrom et al. 1976 [ 11 ] 12y/F Yes Abdominal pain, nausea Clinical 8700 U/l-NA NA No Symptomatic Recovered Werbitt et al. 1980 [ 12 ] 16y/M Yes Abdominal pain, nausea, vomiting VCA positivity 378 U/l-NA CT: no pancreatic abnormality No Not available Recovered Koutras et al. 1983 [ 13 ] 8y/F Yes Abdominal pain, vomiting VCA IgM positivity 300–180 U/l NA Cholestatic hepatitis, proctitis Symptomatic Recovered Khawcharoenporn et al. 2008 [ 14 ] 18y/F Yes Abdominal pain VCA IgM positivity 620–659 U/l CT: edematous pancreas Cholecystitis, septic shock, DIC Symptomatic Recovered Kang et al. 2013 [ 15 ] 11y/F No Abdominal pain, vomiting VCA IgM positivity 4010–4941 U/l CT: edematous pancreas, peripancreatic fluid accumulation Cholestatic hepatitis Fasting, parenteral nutrition Recovered López-Ibáñez et al. 2013 [ 16 ] 15y/M Yes Abdominal pain Heterophil antibody 1251 U/I-NA CT: globular pancreas, hepatosplenomegaly, ascites No Not available Recovered Galzerano et al. 2014 [ 17 ] 3y/F No Abdominal pain VCA IgM positivity 3880 U/l-NA CT: enlargement of the pancreatic head Bilateral pneumonia, portal vein thrombosis, septic shock Fasting, parenteral nutrition, meropenem, teicoplanin, ganciclovir Recovered Narchi et al. 2014 [ 18 ] 8y/M Yes Abdominal pain, vomiting VCA IgM positivity 80–1000 U/l MRI: not visible pancreas Cholestatic hepatitis, cholecystitis Fasting, intravenous fluids Recovered Hammami et al. 2019 [ 8 ] 18y/F Yes Abdominal pain, nausea VCA IgM positivity 327–2016 U/l CT: signs of acute pancreatitis Hepatitis Symptomatic Recovered Our case 3y/F No Abdominal pain, vomiting VCA IgM positivity 913–6450 U/l US: enlargement of the pancreas No Fasting, parenteral nutrition, analgesics Recovered Abbreviations : y years, M Male, F Female, NA Not available, DIC Disseminated intravascular coagulopathy Clinical data of pediatric cases with EBV-associated acute pancreatitis reported in literature and our case VCA IgM positivity VCA IgM positivity VCA IgM positivity Abdominal pain, vomiting Abbreviations : y years, M Male, F Female, NA Not available, DIC Disseminated intravascular coagulopathy As regards adult patients (Table II ), EBV-associated acute pancreatitis affects mainly young adults (range 21–45 years), with a slight female predominance (66%). All cases presented abdominal pain, associated sometimes with nausea, fever, and vomiting. In 3 patients (50%), signs and symptoms related to infectious mononucleosis were also observed. The diagnosis of EBV infection was made by positive serology in 5 patients; also in 2 cases, serum EBV-DNA was detected. Abdominal CT was executed in 5 patients, revealing signs of acute pancreatitis, such as enlarged and edematous pancreas; in 1 case, areas of necrosis were also noticed. All patients except one had complications related to systemic EBV infection, revealing a more severe clinical course in adults than children. The reported complications are hepatitis with or without cholestasis, gastritis, pneumonia with pleural effusion, ascites, pericardial effusion, autoimmune hemolytic anemia, and multi-organ failure. The patients were treated with symptomatic therapy; antibiotics, antivirals, and steroids were also administered in critical cases. All patients except one fully recovered. Table II Clinical data of adult cases with EBV-associated acute pancreatitis reported in literature Reference Age/sex Mononucleosis symptoms Gastrointestinal symptoms EBV diagnosis Amylase-lipase Imaging Other complications Therapy Outcome Jahann et al. 2012 [ 19 ] 22y/M Yes Abdominal pain VCA IgM positivity 330–2300 U/l NR No Symptomatic Recovered Cook et al. 2015 [ 20 ] 25y/M No Abdominal pain, nausea, fever VCA IgM positivity NA-429 U/l CT: pancreatic edema Cholestatic hepatitis, pleural effusions, ascites Fasting, parenteral nutrition, analgesics Recovered Singh et al. 2015 [ 21 ] 21y/F Yes Abdominal pain, vomiting, nausea VCA IgM positivity NA-4301 U/l CT: pancreatic edema Autoimmune hemolytic anemia Symptomatic, prednisone Recovered Zhu et al. 2017 [ 9 ] 35y/F Yes Abdominal pain, vomiting VCA IgM positivity 1300–1450 U/l CT: pancreatic edema Hepatitis, pneumonia Fasting, parenteral nutrition, amoxicillin-clavulanate, acyclovir Recovered Fiani et al. 2021 [ 22 ] 35y/F No Abdominal pain, fever VCA IgM and IgG positivity, serum EBV DNA 129/408 U/l CT: enlargement of the pancreas Cholestatic hepatitis, pneumonia with pleural effusions Symptomatic, linezolid, meropenem, oseltamivir, acyclovir, methylprednisolone Recovered Huang et al. 2021 [ 23 ] 45y/F No Abdominal pain Serum EBV DNA Increased up to three times the normal limit CT: pancreatic necrosis Pericardial and pleural effusions, gastritis, MOF Symptomatic Dead Abbreviations: y years, M Male, F Female, NA Not available, NR Not reported, MOF Multi-organ failure Clinical data of adult cases with EBV-associated acute pancreatitis reported in literature Abbreviations: y years, M Male, F Female, NA Not available, NR Not reported, MOF Multi-organ failure In conclusion, EBV infection is characterized by clinical heterogeneity; multiple organs could be involved, also the pancreas, both in children and young adults. Active surveillance is needed for prompt diagnosis and early treatment. In patients with signs and symptoms of acute pancreatitis, EBV infection should always be considered, even in the absence of the typical clinical and hematological features of infectious mononucleosis. Generally, EBV-associated acute pancreatitis is characterized by a favorable prognosis, with a spontaneous resolution.