Acute acalculous cholecystitis (AAC) is a rare complication of infectious mononucleosis (IM). An immunocompetent 6-year-old Japanese girl complained of epigastralgia during the course of IM. Ultrasonography (US) revealed a markedly thickened and sonolucent gallbladder wall. No gallstones were apparent. Antibodies against Epstein-Barr virus (EBV) confirmed primary EBV infection. Cytomegalovirus immunoglobulin M showed a false-positive result in the acute phase, probably due to cross-reaction to EBV nuclear antigen. We diagnosed her as AAC related with primary EBV infection. She recovered completely by conservative treatment. US should be performed in consideration of the possibility of AAC when a patient with IM complains of epigastralgia

Goji, Aya

Inoue, Miki

Kawahito, Masami

Matsuura, Sato

Mori, Kazuhiro

Shono, Miki

Suga, Kenichi

Tokushima University Institutional Repository

INTRODUCTIONCholecystitis is rare in children. When a patientcomplains of epigastralgia, pediatricians may con-sider possibilities such as enterocolitis, duodenalulcer, and Henoch-Schönlein purpura. On the otherhand, infectious mononucleosis (IM) associated withprimary Epstein-Barr virus (EBV) infection is veryfamiliar, but diagnosis is sometimes difficult dueto the unclear symptoms. IM uncommonly causescomplications such as hemophagocytic lympho-hystiocytosis, splenic rupture, and encephalitis (1).The present study describes a case of acute acal-culous cholecystitis (AAC) associated with IM.CASE REPORTA 6-year-old Japanese girl was admitted to ourhospital with a 10-day history of epigastralgia andlow-grade fever. She had visited a local hospitaltwice and had been subscribed antibiotics for en-terocolitis. Her past history was not significant ex-cept for dysphonia, leading to speech therapy at thelocal hospital. She had not previously experiencedrepeated abdominal pain. Appetite had remaineddecreased since disease onset. Physical examinationshowed that body temperature was 37.3, slightfacial edema was apparent, the mucous membraneof the pharynx was reddened, and some of the cer-vical lymph nodes were swollen. Localized tender-ness was identified in the right hypochondrium with-out enlargement of the liver or spleen. Jaundice wasnot observed in the skin or conjunctiva.Blood examination showed the following : whiteblood cell (WBC) count, 13.6103/μl (atypical lym-phocytes, 1.0%) ; hemoglobin, 12.2 g/dl ; plateletcount, 17104/μl ; C-reactive protein level, 0.6 mg/CASE REPORTA case of acute acalculous cholecystitis complicated byprimary Epstein-Barr virus infectionKenichi Suga, Miki Shono, Aya Goji, Sato Matsuura, Miki Inoue, Masami Kawahito,and Kazuhiro MoriDepartment of Pediatrics, Tokushima Prefectural Central Hospital, Tokushima, JapanAbstract : Acute acalculous cholecystitis (AAC) is a rare complication of infectious mono-nucleosis (IM). An immunocompetent 6-year-old Japanese girl complained of epigastralgiaduring the course of IM. Ultrasonography (US) revealed a markedly thickened and sono-lucent gallbladder wall. No gallstones were apparent. Antibodies against Epstein-Barrvirus (EBV) confirmed primary EBV infection. Cytomegalovirus immunoglobulin M showeda false-positive result in the acute phase, probably due to cross-reaction to EBV nuclearantigen. We diagnosed her as AAC related with primary EBV infection. She recovered com-pletely by conservative treatment. US should be performed in consideration of the pos-sibility of AAC when a patient with IM complains of epigastralgia. J. Med. Invest. 61 : 426-429, August, 2014Keywords : acute acalculous cholecystitis, Epstein-Barr virus, infectious mononucleosisReceived for publication April 11, 2014 ; accepted June 6, 2014.Address correspondence and reprint requests to Kenichi Suga,Department of Pediatrics, Tokushima Prefectural Central Hos-pital, 1 -10-3 Kuramotocho, Tokushima, Tokushima 770-8539,Japan and Fax : +81-88-637-8354.The Journal of Medical Investigation Vol. 61 2014426dl ; aspartate aminotransferase (AST), 184 U/l ;alanine aminotransferase (ALT), 139 U/l ; lactatedehydrogenase (LDH), 559 U/l ; total bilirubin,0.4 mg/dl ; direct bilirubin, 0.1 mg/dl ; γ -glutamyltransferase, 36 U/l ; alkaline phosphatase, 506 U/l ;and leucine aminopeptidase, 86 U/l. Ultrasonogra-phy (US) revealed marked thickening of the gall-bladder wall to 4.6 mm with a sonolucent layer(Fig. 1 A, B). Sludge and pericholecystic fluid wasalso evident. In addition, localized tenderness wasfound over the gallbladder, representing a positivesonographic Murphy’s sign. No stones or dilatationof the biliary tract were evident. Computed tomogra-phy suggested acute hepatitis or cholecystitis withcollapse of the gallbladder, edematous gallbladderwall, and periportal collar sign ; edematous inflam-mation around the portal veins (Figure 2).AAC was diagnosed based on the ultrasonographyfindings. A fat-restricted diet and peripheral infusionwere initiated. IM was also suspected based on theclinical presentation with edematous eyelids, pharyn-gitis, lymphadenopathy, and liver injury. On hospi-tal day 3, the ratio of atypical lymphocytes amongleukocytes was elevated to 8%. Titers of antibodiesto EBV using an indirect immunofluorescence assay(FA) were increased as follows : EBV-viral capsidantigen (VCA) immunoglobulin (Ig)M 1 : 10 ; andEBV-VCA-IgG 1 : 80. EBV-EBNA (FA) was equivo-cal due to non-specific reaction. Anti-cytomegalovi-rus (CMV) antibody levels by enzyme immunoas-say were also elevated as follows : CMV-IgM, 3.43index (normal, 0-0.8) and CMV-IgG, 13.2 index(normal, 0-1.9). Abdominal pain and low-grade fe-ver gradually improved. On hospital day 8, abdomi-nal pain became mild and blood results improvedas follows : WBC count, 11.9103/μl ; AST, 46 U/l ; ALT, 55 U/l ; ALP, 600 U/l ; LDH, 477 U/l ; andCRP, 0.5 mg/dl. On repeated US, thickening of thegallbladder wall was markedly improved (Fig. 1 C.D). The patient was therefore discharged on day 8.At the 1 month follow-up, the patient appearedhealthy and blood results had all normalized. Follow-up after 3 months revealed that EBV-IgG (FA) hadsignificantly increased to 1 : 320 and positive resultsfor EBNA were obtained from enzyme-linked im-munoassay, whereas CMV-IgM was 1.0 index andCMV-IgG had decreased to 11.7 index.Figure 1. Ultrasonography on admission demonstrates sonolucent thickening of the entire circumference of the gallbladder wall, to4.6 mm. (A) Horizontal view. B) Sagittal view. ) Thickening of the gall bladder wall appears on ultrasonography to have resolved byhospital day 8. (C) Horizontal view. D) Sagittal view.)The Journal of Medical Investigation Vol. 61 August 2014 427DISCUSSIONAcute cholecystitis is a rare disease in children.Most adult patients with cholecystitis show compli-cations of gallstones and require emergency sur-gery. In children, acute cholecystitis occurs in rela-tion to infection rather than to gallstones. Reportedassociated pathogens include hepatitis A, Brucella ,malaria, and Salmonella (2, 3). Some reports havedescribed AAC following systemic diseases, includ-ing systemic lupus erythematosus, nephrotic syn-drome, and Kawasaki disease (4, 5). AAC associ-ated with EBV infection has also been reported, butas far as we know, only eight child patients, includ-ing the present case, have been described (6, 7).US examination allowed definitive diagnosis ofAAC. Our patient had been misdiagnosed with en-terocolitis until US was performed at our hospital.US of AAC showed thickening of the gallbladderwall (3 mm), sludge, sonographic Murphy’s sign,and pericholecystic fluid (7). None of these featuresare specific for AAC, combinations of two or moreand clinical symptoms are satisfactory for reachingthe diagnosis of AAC (7). Gallbladder wall thicken-ing is also familiar in various nonbiliary disorders ;viral hepatitis without cholecystitis, peritonitis, livercirrhosis, chronic heart failure, and chronic renalfailure (8). The exact pathophysiologic mechanismleading to the gallbladder wall thickness in suchconditions is uncertain, but it is likely due to venousocclusion of gallbladder wall by elevated portal ve-nous pressure, decreased intravascular osmoticpressure, or subserosal edema, rather than incom-plete gallbladder constriction (8).The etiology of EBV-associated AAC is unknown.Dehydration or direct virus invasion to the bile ductis postulated to be related to the pathogenesis (7).Patients with IM sometimes show loss of appetitedue to sore throat or malaise. Dehydration maycause cholecystitis due to increased bile viscosity.Two cases of EBV-related AAC with Gilbert’s syn-drome were recently reported from Greece (9). Inthe present patient, UGTA gene analysis was notperformed because jaundice did not appear.Most children with EBV-associated AAC presentwith mild clinical symptoms and good prognosis,whereas adult EBV-associated AAC sometimes pro-gresses to serious conditions such as gallbladderperforation, pulmonary edema, or hepatic failure(10).Co-infection with EBV and CMV was considereddue to the positive IgM for both in the acute phase,but follow-up examinations eventually confirmedprimary EBV infection, while CMV infection wasruled out because the CMV IgG titer showed nosignificant increase. Regrettably, we did not performCMV-DNA analysis using polymerase chain reac-tion. A previous report described false-positive re-sults for CMV IgM during primary EBV infection(11). We thus suggest that EBNA might cross-reactwith CMV IgM, resulting in EBNA showing a non-specific reaction and CMV IgM showing a false-positive result.In conclusion, US should be performed when apatient complains of right upper quadrant pain dur-ing the course of IM, in consideration of the possi-bility of AAC. It makes it possible to avoid unnec-essary examinations, treatments, and administrationof antibacterial agents.We declare that conflict of interest is none.Figure 2. Plain computed tomography on admission suggests acute hepatitis or cholescystitis.A. Low density area is observed around the portal veins. (Periportal collar sign)B. Edematous swelling of gallbladder wall was shown by arrow. Low echoic lesions surrounded high echoic lesions in gallbladder.K. Suga, et al. acalculous cholecystitis by EBV infection428REFERENCES1. Jenson HB. Epstein Barr virus. Nelson text-book of pediatrics. 16 th edition chapter 247,p977-981.Behman RE, Kiegman RM, JensonHB (eds)2. 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A case of acute acalculous cholecystitis complicated by primary Epstein-Barr virus infection

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A case of acute acalculous cholecystitis complicated by primary Epstein-Barr virus infection

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