Case Report Acute Acalculous Cholecystitis Due to a Primary Epstein Barr Virus Infection in a Pediatric Patient Carlos Leganés Villanueva 1, *, Ilaria Goruppi 1 , Nuria Brun Lozano 1 , Federica Bianchi 1 , María Quinteiro González 2 and Susana Boronat Guerrero 2 1 Pediatric Surgery Unit, Department of Pediatrics, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain; igoruppi@santpau.cat (I.G.); nbrun@santpau.cat (N.B.L.); fbianchix@santpau.cat (F.B.) 2 Pediatric Unit, Department of Pediatrics, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain; mquinteiro@santpau.cat (M.Q.G.); sboronat@santpau.cat (S.B.G.) * Correspondence: cleganes@santpau.cat; Tel.: +34-932-91-90-00 Abstract: Epstein–Barr virus (EBV) is estimated to infect more than 98% of adults worldwide and is one of the most common human viruses. Acute acalculous cholecystitis (AAC) of the gallbladder is an atypical complication of infectious mononucleosis caused by EBV. Conservative management has been described in the context of AAC caused by EBV. A surgical approach must be considered in the case of acute complications such as perforation or gallbladder gangrene. We present the case of a 10-year-old female patient with AAC due to infectious mononucleosis syndrome caused by primary EBV infection. Keywords: acute acalculous cholecystitis; Epstein Barr virus; conservative management; infectious   mononucleosis; pediatrics Citation: Leganés Villanueva, C.; Goruppi, I.; Brun Lozano, N.; Bianchi, F.; Quinteiro González, M.; Boronat Guerrero, S. Acute Acalculous 1. Introduction Cholecystitis Due to a Primary Acute acalculous cholecystitis (AAC) is a gallbladder infection not related to gallstones, Epstein Barr Virus Infection in a leading to serious consequences. AAC is caused by gallbladder stasis from hypomotility Pediatric Patient. Pediatr. Rep. 2021, that leads to increased intraluminal pressures in the gallbladder wall, resulting in ischemia, 13, 86–90. https://doi.org/ inflammation, and potential necrosis [1]. Only 5–10% of acute cholecystitis cases are 10.3390/pediatric13010011 AAC in adults, and they have higher morbidity and mortality than calculous cholecystitis. Acute inflammatory gallbladder diseases including ACC are relatively uncommon in Received: 23 April 2020 pediatric patients [2]. Accepted: 1 February 2021 Acute infection with Epstein–Barr virus (EBV) is a common disease mainly affecting Published: 6 February 2021 adolescents and young adults and it is usually asymptomatic; it often presents as typical infectious mononucleosis symptoms such as fever, sore throat, cervical lymphadenopa- Publisher’s Note: MDPI stays neutral thy, and hepatosplenomegaly. Hepatic involvement is very common and AAC may oc- with regard to jurisdictional claims in cur during acute primary EBV infection, which is rarely encountered in the pediatric published maps and institutional affil- population [3]. iations. To date, only 24 cases of AAC caused by EBV infection have been reported in pedi- atrics [4]. In this report, we present a case of primary EBV infection complicated by AAC in a 10-year-old patient. Copyright: © 2021 by the authors. 2. Case Report Licensee MDPI, Basel, Switzerland. A 10-year-old female was brought to the emergency department complaining of a This article is an open access article 7-day history of low-grade fever up to 38.5 ◦ C, sore throat, mild cough, sharp abdominal distributed under the terms and pain, mainly in the right abdominal area, and nausea. Physical examination revealed conditions of the Creative Commons sensitivity to palpation in the right hypochondriac and lumbar regions and epigastrium, Attribution (CC BY) license (https:// normal bowel sounds, and no abdominal distention. creativecommons.org/licenses/by/ 4.0/). Pediatr. Rep. 2021, 13, 86–90. https://doi.org/10.3390/pediatric13010011 https://www.mdpi.com/journal/pediatrrep Pediatr. Pediatr.Rep. 2021,1313, FOR PEER REVIEW Rep.2021, 872 Additionally, Additionally,bilateral bilateralcervical cervicaland andaxillary axillarylymphadenopathy, lymphadenopathy,tonsillar tonsillarhypertrophy hypertrophy without withoutexudates, exudates, andandaapalpable palpablehepatosplenomegaly hepatosplenomegaly were were noticed, noticed, andandthere therewas wasno no conjunctival conjunctivalicterus. icterus. Laboratory Laboratorystudies studiesshowed showedaawhite whiteblood bloodcellcellcount 7200××10 countofof7200 1033 per per microliter microliter(µL) (μL) 3 (4.5–14.5×× 103/μL), (4.5–14.5 /µL),aaC-reactive C-reactiveprotein proteinlevel levelofof 16.2 16.2 milligrams milligrams perper deciliter deciliter (mg/dL) (mg/dL) (3–5 (3–5 mg/dL), a total bilirubin level of 29 µg/L (0–17 µg/L) with direct bilirubin mg/dL), a total bilirubin level of 29 μg/L (0–17 μg/L) with direct bilirubin of 10 μg/L (0–6 of 10 µg/L (0–6 µg/L), μg/L), an alkaline an alkaline phosphatase phosphatase (ALP) (ALP) levelofof642 level 642units units per liter liter (U/L) (U/L) (35–110 (35–110U/L), U/L), gamma-glutamyl transferase (GGT) levels of 297 U/L (1–48 U/L), gamma-glutamyl transferase (GGT) levels of 297 U/L (1–48 U/L), glutamic-pyruvic glutamic-pyruvic transaminase transaminase (GPT) (GPT) levels of 301 levels of 301 U/L U/L(1–31 (1–31U/L), U/L), andand glutamic-oxaloacetic glutamic-oxaloacetic transami- transaminase nase (GOT)(GOT) levels levels of U/L of 279 279 U/L (1–31(1–31 U/L).U/L). Formal Formal abdominal ultrasonographyrevealed abdominal ultrasonography revealedaathickening thickeningofofthethe gallbladder gallbladder wallwall (4.5 (4.5 mm) and pericholecystic edema (Figure 1). Distention of the gallbladder mm) and pericholecystic edema (Figure 1). Distention of the gallbladder was not evident, was not evident, and no and no stones orstones or dilatation dilatation of the of the biliary biliary tract were tract wereBased reported. reported. Based on these on these findings, the findings, the diagnosis of acute acalculous cholecystitis was made diagnosis of acute acalculous cholecystitis was made and the patient was admitted to and the patient wasthe admitted pediatricstodepartment the pediatrics fordepartment for furtherand further investigation investigation treatment. and treatment. Figure1.1.Abdominal Figure Abdominalultrasonography ultrasonographyshowing showingaathickening thickeningof ofthe thegallbladder gallbladderwall wallof of4.5 4.5mm mmand and pericholecystic edema. pericholecystic edema. Thepatient The patientwaswas treated treated with and with fasting fasting and intravenous intravenous rehydration. Her rehydration. cardiovascularHer cardiovascular and and respiratory respiratory function remained function remained stable. Blood and stable. Blood and urine cultures wereurine cultures negative. were Serolog- negative. ical Serological tests, both tests, antibody heterophile both heterophile test andantibody test andagainst IgM antibodies IgM antibodies EBV capsid against EBV antigen, confirmed the diagnosis of infectious mononucleosis. Serological tests for hepatitis A, B, for capsid antigen, confirmed the diagnosis of infectious mononucleosis. Serological tests C, hepatitis CMV, HIV,A,and B, C, CMV, HIV, Toxoplasma andwere gondii Toxoplasma negative. gondii were negative. Twodays Two daysafter afteradmission, admission,the thepatient patienthadhadaagoodgoodclinical clinicalstatus, status,fever feverwas wasresolved, resolved, enteral nutrition enteral nutrition waswas restarted, restarted, and andthetheabdominal abdominalpain painhadhadalsoalsodisappeared. disappeared. In Inthe the laboratory test on laboratory on day day3,3,a atotal bilirubin total bilirubin(B)(B) level of 19 level ofμg/L with direct 19 µg/L bilirubin with direct of 7 μg/L, bilirubin of 7an alkaline µg/L, phosphatase an alkaline phosphatase(ALP)(ALP) levellevel of 199 of 199units unitsper per liter (U/L), gamma-glutamyl liter (U/L), gamma-glutamyl transferase(GGT) transferase (GGT)levels levelsofof48 48U/L, U/L,glutamic-pyruvic glutamic-pyruvictransaminase transaminase(GPT) (GPT)levels levelsofof1919U/L U/L andglutamic-oxaloacetic and glutamic-oxaloacetictransaminase transaminase(GOT) (GOT)levels levelsofof22 22U/L U/L were were observed. observed. The Thepatient patientwaswasdischarged discharged onon day 4 with day 4 witha good clinical a good status. clinical TwoTwo status. weeks later,later, weeks a clin-a ical control clinical in the outpatient control department in the outpatient revealed norevealed department clinical ornolaboratory clinical abnormalities or laboratory and an abdominal abnormalities andultrasound an abdominal revealed a total remission ultrasound revealedof a the totalprevious abnormal remission of the findings. previous After 6 months abnormal findings. of follow up, the patient remains asymptomatic. After 6 months of follow up, the patient remains asymptomatic. Pediatr. Rep. 2021, 13 88 3. Discussion Epstein–Barr virus (EBV) infection can lead to infectious mononucleosis syndrome with the typical symptoms of fever, pharyngitis, lymphadenopathy, and hepatosplenomegaly. However, cholecystitis is not usually considered part of a primary EBV infection and ultrasound scan (USS) of the liver and gallbladder is not routinely performed [5]. In our case, we performed the USS in order to identify a possible inflammation of the appendix because abdominal pain on the right abdominal side. Acute acalculous cholecystitis (AAC) is a gallbladder infection not related to gallstones. It is more frequently found in males and represents 5–10% of all cases of acute cholecystitis in adults. Cholecystitis in children is not common (Tsakayannis et al. estimated 1.3 pediatric cases for every 1000 cases in adults) and 30–50% of these patients are AAC [6]. To our knowledge, only a few cases of EBV-associated AAC have been described in pediatric patients (Table 1). Table 1. Cases of Epstein–Barr virus-associated acute acalculous cholecystitis in pediatric patients. Author Year Age Sex Antibiotic Surgery Favorable Outcome Yoshie et al. [7] 2004 15 F - No Yes Lagona et al. [8] 2007 4 F No No Yes Prassouli et al. [9] 2007 13 F Yes No Yes Gora-Gebka et al. [10] 2008 9 F Yes No Yes Gora-Gebka et al. [10] 2008 4 F Yes No Yes Pelliccia et al. [11] 2008 14 F No No Yes Attilakos et al. [12] 2009 5 F Yes No Yes Attilakos et al. [12] 2009 4 M No No Yes Arya et al. [13] 2010 16 F Yes No Yes Aydin Teke et al. [14] 2013 8 F No No Yes Fretzayas et al. [15] 2014 11 F - No Yes Fretzayas et al. [15] 2014 12 F - No Yes Kim et al. [3] 2014 10 F Yes No Yes Poddighe et al. [16] 2014 7 F Yes No Yes Suga et al. [17] 2014 6 F Yes No Yes Alkhoury et al. [18] 2015 15 F No No Yes Shah et al. [19] 2015 6 F Yes No Yes Branco et al. [20] 2015 16 M Yes No Yes Majdalani et al. [21] 2016 16 F Yes No Yes Say et al. [22] 2016 14 F Yes No Yes Rodà et al. [23] 2017 2 M Yes No Yes Graber et al. [24] 2018 15 F Yes Yes No Young et al. [4] 2019 14 F Yes No Yes Present case 2020 10 F No No Yes Among the age-related predisposing diseases, systemic infectious diseases such as EBV were the most common ones in middle childhood and adolescence [25]. The exact pathogenesis of EBV-associated AAC is unclear; EBV-associated hepatitis is recognized as an important cause of cholestasis, suggesting that acute infection may induce the bile stasis and subsequent gallbladder inflammation that led to the development of AAC [22]. In children, AAC occurs more frequently during the course of infectious diseases such as sepsis, gastroenteritis (including Vibrio cholerae, Salmonella spp, Shigella spp, and Giar- dia lamblia), pneumonia (especially due to Mycoplasma pneumoniae), cytomegalovirus pri- mary infection, hepatitis A, Dengue, infection secondary to non-tuberculous mycobacteria, leptospirosis, Q-fever, Candida, malaria, and HIV infection. It has also been associated with Pediatr. Rep. 2021, 13 89 the use of parenteral nutrition, post-surgery, extensive burns, and after trauma. In healthy patients such as the related case, this form of cholecystitis is even less frequent [6,26]. The diagnosis of AAC in children remains a clinical challenge, especially in critical patients. Clinical, laboratory, and imaging findings will finally lead to diagnosis. Clinical presentation has been reviewed, concluding that right upper quadrant abdominal pain and fever remains the most common symptoms. Sore throat and pharyngitis, cervical lym- phadenopathy, abdominal tenderness, and Murphy’s sign are also common findings. Eleva- tion of GGT, GOT, ALP, and bilirubin in various degrees was also reported [27]. After three days of hospital stay, our patient presented decreasing GGT, GPT and GOT values within the reference range. After two weeks of follow up, B and ALK were also normalized. We performed a review of the abdominal sonographic findings in pediatric patients with EBV-associated AAC, and it has been related the sonographic gallbladder wall thick- ening greater than 3 mm, hepatomegaly, splenomegaly, increased periportal echogenicity, and periportal lymph nodes [28]. Pericholecystic fluid (halo) or subserosal edema, intramu- ral gas or hydrops and the presence of echogenic bile have also been described. In uncertain cases, computed tomography and cholescintigraphy using 99mTc are reasonable imaging alternatives to establish the diagnosis [26,28]. In children with AAC due to EBV, medical treatment should be considered the manage- ment of choice; excellent recovery without surgical treatment is generally expected. The use of intravenous antibiotics is controversial, and emergency surgical intervention should only be considered if ultrasonographic abnormalities persist or worsen on follow-up exam- inations [23]. In our case, we proposed intravenous fluids, nonsteroidal anti-inflammatory drugs, and rest, with excellent recovery in two days. The incidence of complications in AAC for EBV is low when prompt and accurate diagnosis and treatment are performed. If the diagnosis is delayed or incorrect, compli- cations such as perforation and gangrene have been described. Graber et al. presented the case of a 15-year-old female who underwent laparoscopic cholecystectomy for EBV- associated AAC and died after surgery due to unexplained postoperative complications. Furthermore, poor predictors of AAC mortality include the presence of thrombocytopenia, anemia, gallbladder sludge, associated hepatitis, and sepsis plus hepatitis [24,29]. 4. Conclusions Despite AAC being a rare complication of infectious mononucleosis for EBV in chil- dren, a high index of suspicion is important for the diagnosis, especially in patients without a relevant past medical history. 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