Journal of Clinical Virology 61 (2014) 173–175
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case Report
Acute acalculous cholecystitis, a rare complication of Epstein–Barr virus primary infection: Report of two cases and review Amandine Gagneux-Brunon a,b,∗ , Florence Suy a,b , Anne Pouvaret a , Sylvie Pillet b,c , Enrico Tarantino d , Dorothée Bouchet e , Anne Fresard a,b , Céline Cazorla a , Claire Guglielminotti a , Frédéric Lucht a,b , Elisabeth Botelho-Nevers a,b a
Department of Infectious and Tropical Diseases, Universitary Hospital of Saint-Etienne, Saint-Etienne, France Groupe Immunité des Muqueuses et Agents Pathogènes, EA 3064, Université Jean-Monnet, Université de Lyon, Saint-Etienne, France c Laboratoire de bactériologie et Virologie, Universitary Hospital of Saint-Etienne, Saint-Etienne, France d Department of General Surgery, Universitary Hospital of Saint-Etienne, Saint-Etienne, France e Department of Radiology, Universitary Hospital of Saint-Etienne, Saint-Etienne, France b
a r t i c l e
i n f o
Article history: Received 5 February 2014 Received in revised form 27 May 2014 Accepted 30 May 2014
a b s t r a c t We described two cases of acalculous cholecystitis (AAC), due to EBV primary infection in two young caucasian women and we reviewed other reported cases. In contrast with AAC of other etiologies, antibiotics and surgery are not useful in the management of AAC secondary to EBV. © 2014 Elsevier B.V. All rights reserved.
1. Case importance
2. Cases description
In children primary Epstein–Barr virus (EBV) infection is often asymptomatic. In economically developed countries, EBV primary infection delayed until adolescence or later. A great proportion of young adults, who experience EBV primary infection, presents as clinical mononucleosis with sore throat, fever, fatigue and lymphadenopathy (IM) (77%) [1]. Abnormal liver function tests and clinical jaundice have been reported respectively in 80% and 5% of the cases whereas fulminant hepatitis remained rare [2]. Radiologists described gallbladder wall thickening associated with severe IM [3] however only few cases of real acute acalculous cholecystitis (AAC) have been described in EBV primary infection. AAC is frequently described in critically ill patients and is associated with a poor prognosis in this context [4]. We report here two cases of AAC during EBV primary infection in 2 young women. We also performed a literature search using Medline database with the following terms: “gallbladder and EBV”, “gallbladder and infectious mononucleosis”, “cholecystitis and EBV” or “acalculous cholecystitis” in the aim of identify other similar cases.
2.1. Case 1
∗ Corresponding author at: Department of Infectious and Tropical Diseases, Universitary Hospital of Saint-Etienne, Saint-Etienne, France. Tel.: +33 477120356. E-mail address: [email protected] (A. GagneuxBrunon). http://dx.doi.org/10.1016/j.jcv.2014.05.019 1386-6532/© 2014 Elsevier B.V. All rights reserved.
A previously healthy Caucasian, 18 year-old woman was admitted to our institution with a 7-day history of high grade fever and asthenia. On admission, physical examination revealed: fever (38.5 ◦ C), normal blood pressure (114/65 mmHg), pulse rate was 98/min, respiration rate 18/min, cervical lymph nodes were enlarged. Tonsil and pharynx were normal at examination. On examination of the abdomen, the right upper quadrant was tender and painful. Neither enlargement of spleen nor liver was found, a discrete erythematous papulous rash on limbs was observed mainly during febrile peaks. The rest of the examination was normal. Laboratory findings showed a white blood cells count of 6.36 × 109 /L (32.5% of neutrophils, 30.5% of lymphocytes, and 28.4% of activated lymhocytes), platelets 121 × 109 /L, aspartate aminotransferase (AST) 321 UI/L, alanine aminotransferase (ALT) 214 UI/L, alkaline phosphatase (ALP) 165 UI/L, gammaglutamyl transferase (GGT) 64 UI/L, total bilirubin 20 mol/L, lactate dehydrogenase (LDH) 1838 UI/L. At day 1 of the admission, the first abdominal ultrasonography performed was normal. Serology for EBV showed positive anti-EBV VCA IgM and anti-EBV VCA IgG and negative anti-EBV EBNA IgG confirming primary EBV infection. Search for heterophile antibodies was positive. Two days later, the right upper quadrant abdominal pain increased with a Murphy’s sign at physical examination. Laboratory
174
A. Gagneux-Brunon et al. / Journal of Clinical Virology 61 (2014) 173–175
her admission. Liver enzymes remained increased for two months after admission, and white blood cells count return to normal after three months. Fatigue disappeared after three weeks.
3. Other similar and contrasting cases in the literature
Fig. 1. Gallbladder wall thickening and microabcess in the context of acalculous cholecystitis due to EBV primary infection (Case 1).
findings showed a similar degree of liver enzyme levels compared to admission. A second abdominal ultrasonography showed a striated thickened gall bladder wall (12 mm) with micro-abscesses without lithiasis, suggesting an acute acalculous cholecystitis (see Fig. 1). Intravenous rehydration therapy and antibiotic treatment with ceftriaxone 2 g by day and metronidazole (1500 mg a day) were started due to the risk of perforation of the gallbladder. Digestive surgeons temporized a surgical intervention but examined the patient every day until discharge. At day 7, the abdominal pain disappeared and gallbladder appeared normal at abdominal ultrasonography. Antibiotic therapy was stopped, and the patient was discharged on the eighth day following admission. At day 35, a new ultrasonography and laboratory findings were normal. 2.2. Case 2 A previously healthy Caucasian, 20 year-old woman was admitted with a right quadrant abdominal pain, 7 days after a tonsillopharyngitis to the general surgery department of our institution. On admission, physical examination revealed: moderate jaundice, fever, 38.5 ◦ C, blood pressure, 114/65 mmHg, pulse rate 98/min, respiration rate 18/min, only cervical lymph nodes were enlarged but not inflammatory, tonsil and pharynx were normal, neurological examination was normal. On examination of the abdomen, the right upper quadrant was tender and painful. Spleen and liver were not enlarged. Laboratory findings showed a white blood cells count of 11.52 × 109 /L (14.2% of neutrophils, 41.6% of lymphocytes, and 38.1% of activated lymhocytes), platelets 139 × 109 /L, aspartate aminotransferase (AST) 453 UI/L, alanine aminotransferase (ALT) 494 UI/L, alkaline phosphatase (ALP) 133 UI/L, gammaglutamyl transferase (GGT) 286 UI/L, total bilirubin 38.2 mol/L. An abdominal ultrasonography was performed on the day of the admission, showed an enlarged gallbladder with a gallbladder wall thickened (16 mm) without calculus. In this context, surgeons did not perform a cholecystectomy. An empirical antibiotic treatment was started with amoxicillin and clavulanate (3 g by day). Serologies for cytomegalovirus, HIV, Hepatitis A, B, C, HSV were negative. Serology for EBV revealed that IgG and IgM anti-VCA were positive while IgG anti-EBNA were negative confirming a EBV primary infection, search for heterophile antibodies was positive. Serology for VZV was in favor of an anterior infection. Antibiotics were stopped after the result of EBV serology. Four days later, the abdominal ultrasonography was normal. The patient was discharged 5 days after
In the review that we performed, only 16 other cases were retrieved in PUBMED database showing the rarity of this complication in EBV primary infection [5–17] (Table 1). Acute acalculous cholecystitis contributes to 5–10% of overall cholecystitis. It is usually described in patients with severe trauma and burns, critical illness, cardiovascular surgery [4] and autoimmune disease as lupus. In intensive care, mortality of AAC is high as 40–60%, and surgery is always required [18]. AAC has also been reported during several infectious diseases such as cytomegalovirus primary infection, viral hepatits A, Dengue, infection secondary to non tuberculous mycobacteria, Salmonella spp, leptospirosis, Q-fever, Candida and Malaria [19]. EBV is known to induce elevation of transaminases and jaundice but few data support its association with cholecystitis. Our two cases were very similar to those described in literature. Therefore, the initial clinical presentation (particularly for the first case) was not classical of IM. Table 1 summarized the 16 cases of AAC in the context of EBV primary infection that we found in literature. As highlighted, most of the cases of AAC during EBV primary infection occurred in women (sex ratio 1/16). All the patients were younger than 25 years but only six cases occurred in children under 12 years old (Table 1). This observation may confirm that severe manifestations of EBV primary infection principally occurred in young adults. Patients developing acute acalculous cholecystitis had strong elevation in liver enzymes (Table 1), compared to patients with classical IM, obtained from a series of 114 patients with classical IM [20] (mean AST 515 vs 76.2 UI/L and ALT 552 vs 94.1 UI/L, bilirubin 5.5 vs 0.8 mg/dL). AAC due to EBV primary infection occurred in patients with the highest increase in liver enzymes level. The mechanism of AAC in EBV primary infection is unknown. Most of the authors hypothesized that EBV-induced hepatitis is a cause of cholestasis, inducing gallbladder inflammation and AAC. In the rare AAC reported in children, two of them occurred in children with a Gilbert’s syndrome (GS) [14]. The presence of GS could play a role in the development of gallbladder abnormalities as it is associated with an increase in bilirubin, and since higher level of bilirubin may contribute to AAC in EBV-primary infection. Only one described case had a normal level of bilirubin. In most cases, AAC developed early during the course of the EBV primary infection, 5–7 days after the first clinical signs of IM. In all the cases reported, AAC secondary to EBV primary infection had favorable outcomes. In a majority of cases, antibiotics were prescribed and discontinued after the diagnosis of EBV primary infection was performed. The favorable outcomes of these cases support this attitude. While, AAC is considered as a surgical emergency in critically ill patients, in the case of AAC associated with EBV primary infection, surgical intervention is rarely necessary. In fact in the 16 cases described in Table 1, cholecystectomy was only required in one case, a 22-year old woman, receiving azathioprine for an inflammatory bowel disease [13]. Radiologists first described gallbladder wall thickening in EBV primary infection and proposed it as a sign of severity of infectious mononucleosis [3]. Although EBV primary infections are rarely severe, AAC may cause gallbladder perforation. In conclusion, physicians and digestive surgeons should therefore be aware of the occurrence of AAC during EBV primary infection. When confronted by young patient without past history and presenting an AAC, EBV serology should be performed. Abdominal ultrasonography is also useful in young adults presenting with
No fever Fever, malaise Fever, malaise, pharyngitis
Sore throat, malaise Painful swelling Fever, malaise Fever, malaise, vomiting
Sore throat Sore throat, malaise
Fever, malaise, vomiting Fever, nausea Fever, sore throat Fever, malaise Fever, malaise
None. Competing interests None.
3 7 7
2.5 1.3 4.6
0.9 2.2 300 286
145 103 143 157 133
239 161 434
10 12
+ +
No Yes 48 h No Yes Yes Yes 48 h
5 7 7 5 Yes 24 h
+ + NR NR 5 14 15 0.7 727
299 70 464 166 496 3324 228 494 171 105 329 121 569 3398 244 453
202
2 7 6 8 4.2 4.7 6.5 1.8 584 257
388 220
426 207
156 333
710 919
13.6 9 9 7 9 674 304 179 423 328 394 188
352 241 184 301 142
721 236 629 752 312
4 4.6 4.6 2.9 7
Yes No
Yes Yes Yes 48 h
NR NR NR NR NR NR NR
6 7 1
Yes +
5
Not appropriate, published with the consent of the two patients.
13 4 9 4 18 14 22 22 5 22 20 22 22 29 8 7 18 20 Prassouli et al. [5] Lagona et al. [6] Gora-Gebka et al. [7] Gora-Gebka et al. [7] Iaria et al. [8] Pelliccia et al. [9] Chalupa et al. [10] Cholongitas et al. [11] Attilakos et al. [12] Hagel et al. [13] Yang et al. [14] Dylewski [15] Carrascosa et al. [16] Beltrame et al. [17] Teke et al. [21] Poddighe et al. [22] Case 1 Case 2
F F F F F F F F M F F F F F F F F F
Initial clinical signs before AAC diagnosis Time since the first clinical signs of IM (days) Antibiotics Heterophile ab GWT (mm) Bilirubin (mg/dL) ALP (UI/L) ␥GGT (UI/L) ALT (UI/L) AST (UI/L)
Funding
Ethical approval
Age
Sex
175
right quadrant abdominal pain in the context of EBV primary infection, with a strong elevation in liver enzymes level to confirm AAC. Thanks to this review we could conclude that management of AAC during EBV primary infection require surveillance, and no surgery.
Authors
Table 1 Clinical characteristics and laboratory findings in the 14 described cases of AAC due to EBV primary infection (upper limit values for AST 45 UI/L, ALT 45 UI/L, 80 UI/L for ALP, total bilirubin 10 mg/l, gamma GT 55 UI/L, ab: antibodies, NR: not reported).
A. Gagneux-Brunon et al. / Journal of Clinical Virology 61 (2014) 173–175
References [1] Balfour Jr HH, Odumade OA, Schmeling DO, Mullan BD, Ed JA, Knight JA, et al. Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein–Barr virus infection in university students. J Infect Dis 2013;207:80–8. [2] Macsween KF, Crawford DH. Epstein–Barr virus—recent advances. Lancet Infect Dis 2003;3:131–40. [3] Yamada K, Yamada H. Gallbladder wall thickening in mononucleosis syndromes. J Clin Ultrasound 2001;29:322–5. [4] Wang A-J, Wang T-E, Lin C-C, Lin S-C, Shih S-C. Clinical predictors of severe gallbladder complications in acute acalculous cholecystitis. World J Gastroenterol 2003;9:2821–3. [5] Prassouli A, Panagiotou J, Vakaki M, Giannatou I, Atilakos A, Garoufi A, et al. Acute acalculous cholecystitis as the initial presentation of primary Epstein–Barr virus infection. J Pediatr Surg 2007;42:E11–3. [6] Lagona E, Sharifi F, Voutsioti A, Mavri A, Markouri M, Attilakos A. Epstein–Barr virus infectious mononucleosis associated with acute acalculous cholecystitis. Infection 2007;35:118–9. ´ [7] Gora-Gebka M, Liberek A, Bako W, Szarszewski A, Kaminska B, Korzon M. Acute acalculous cholecystitis of viral etiology – a rare condition in children? J Pediatr Surg 2008;43:e25–7. [8] Iaria C, Arena L, Di Maio G, Fracassi MG, Leonardi MS, Famulari C, et al. Acute acalculous cholecystitis during the course of primary Epstein–Barr virus infection: a new case and a review of the literature. Int J Infect Dis 2008;12:391–5. [9] Pelliccia P, Savino A, Cecamore C, Di Marzio D, Chiarelli F, Primavera A, et al. Imaging spectrum of EBV-infection in a young patient. J Ultrasound 2008;11:82–4. [10] Chalupa P, Kaspar M, Holub M. Acute acalculous cholecystitis with pericholecystitis in a patient with Epstein–Barr virus infectious mononucleosis. Med Sci Monit 2009;15:CS30–3. [11] Cholongitas E, Katsogridakis K, Dasenaki M. Acalculous cholecystitis during the course of acute Epstein–Barr virus infection. Int J Infect Dis 2009;13: e129–30. [12] Attilakos A, Prassouli A, Hadjigeorgiou G, Lagona E, Kitsiou-Tzeli S, Galla A, et al. Acute acalculous cholecystitis in children with Epstein–Barr virus infection: a role for Gilbert’s syndrome? Int J Infect Dis 2009;13:e161–4. [13] Hagel S, Bruns T, Kantowski M, Fix P, Seidel T, Stallmach A. Cholestatic hepatitis, acute acalculous cholecystitis, and hemolytic anemia: primary Epstein–Barr virus infection under azathioprine. Inflamm Bowel Dis 2009;15:1613–6. [14] Yang HN, Hong KW, Lee JS, Eom JS. A case of acute cholecystitis without cholestasis caused by Epstein–Barr virus in a healthy young woman. Int J Infect Dis 2010;14:e448–9. [15] Dylewski J. Acute acalculous cholecystitis caused by epstein-barr virus infection. Clin Microbiol Newslett 2012;34:7–8. [16] Carrascosa MF, Caviedes J-RS, Soler-Dorda G, Saiz-Perez C. Epstein–Barr virus acute cholecystitis. Case Rep 2012;2012, bcr0220125744–bcr0220125744. [17] Beltrame V, Andres A, Tona F, Sperti C. Epstein–Barr virus – associated acute acalculous cholecystitis in an adult. Am J Case Rep 2012;13:153–6. [18] Kalliafas S, Ziegler DW, Flancbaum L, Choban PS. Acute acalculous cholecystitis: incidence, risk factors, diagnosis, and outcome. Am Surg 1998;64:471–5. [19] Barie PS, Eachempati SR. Acute acalculous cholecystitis. Curr Gastroenterol Rep 2003;5:302–9. [20] Grotto I, Mimouni D, Huerta M, Mimouni M, Cohen D, Robin G, et al. Clinical and laboratory presentation of EBV positive infectious mononucleosis in young adults. Epidemiol Infect 2003;131:683–9. [21] Teke TA, Tanır G, Ozel A, Timur OM, Eks¸io˘glu AS. A case of acute acalculous cholecystitis during the course of reactive Epstein–Barr virus infection. Turk J Gastroenterol 2013;24:571–2. [22] Poddighe D, Cagnoli G, Mastricci N, Bruni P. Acute acalculous cholecystitis associated with severe EBV hepatitis in an immunocompetent child. BMJ Case Rep 2014 2014, http://casereports.bmj.com/content/2014/bcr-2013-201166.long.
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case Report
Acute acalculous cholecystitis, a rare complication of Epstein–Barr virus primary infection: Report of two cases and review Amandine Gagneux-Brunon a,b,∗ , Florence Suy a,b , Anne Pouvaret a , Sylvie Pillet b,c , Enrico Tarantino d , Dorothée Bouchet e , Anne Fresard a,b , Céline Cazorla a , Claire Guglielminotti a , Frédéric Lucht a,b , Elisabeth Botelho-Nevers a,b a
Department of Infectious and Tropical Diseases, Universitary Hospital of Saint-Etienne, Saint-Etienne, France Groupe Immunité des Muqueuses et Agents Pathogènes, EA 3064, Université Jean-Monnet, Université de Lyon, Saint-Etienne, France c Laboratoire de bactériologie et Virologie, Universitary Hospital of Saint-Etienne, Saint-Etienne, France d Department of General Surgery, Universitary Hospital of Saint-Etienne, Saint-Etienne, France e Department of Radiology, Universitary Hospital of Saint-Etienne, Saint-Etienne, France b
a r t i c l e
i n f o
Article history: Received 5 February 2014 Received in revised form 27 May 2014 Accepted 30 May 2014
a b s t r a c t We described two cases of acalculous cholecystitis (AAC), due to EBV primary infection in two young caucasian women and we reviewed other reported cases. In contrast with AAC of other etiologies, antibiotics and surgery are not useful in the management of AAC secondary to EBV. © 2014 Elsevier B.V. All rights reserved.
1. Case importance
2. Cases description
In children primary Epstein–Barr virus (EBV) infection is often asymptomatic. In economically developed countries, EBV primary infection delayed until adolescence or later. A great proportion of young adults, who experience EBV primary infection, presents as clinical mononucleosis with sore throat, fever, fatigue and lymphadenopathy (IM) (77%) [1]. Abnormal liver function tests and clinical jaundice have been reported respectively in 80% and 5% of the cases whereas fulminant hepatitis remained rare [2]. Radiologists described gallbladder wall thickening associated with severe IM [3] however only few cases of real acute acalculous cholecystitis (AAC) have been described in EBV primary infection. AAC is frequently described in critically ill patients and is associated with a poor prognosis in this context [4]. We report here two cases of AAC during EBV primary infection in 2 young women. We also performed a literature search using Medline database with the following terms: “gallbladder and EBV”, “gallbladder and infectious mononucleosis”, “cholecystitis and EBV” or “acalculous cholecystitis” in the aim of identify other similar cases.
2.1. Case 1
∗ Corresponding author at: Department of Infectious and Tropical Diseases, Universitary Hospital of Saint-Etienne, Saint-Etienne, France. Tel.: +33 477120356. E-mail address: [email protected] (A. GagneuxBrunon). http://dx.doi.org/10.1016/j.jcv.2014.05.019 1386-6532/© 2014 Elsevier B.V. All rights reserved.
A previously healthy Caucasian, 18 year-old woman was admitted to our institution with a 7-day history of high grade fever and asthenia. On admission, physical examination revealed: fever (38.5 ◦ C), normal blood pressure (114/65 mmHg), pulse rate was 98/min, respiration rate 18/min, cervical lymph nodes were enlarged. Tonsil and pharynx were normal at examination. On examination of the abdomen, the right upper quadrant was tender and painful. Neither enlargement of spleen nor liver was found, a discrete erythematous papulous rash on limbs was observed mainly during febrile peaks. The rest of the examination was normal. Laboratory findings showed a white blood cells count of 6.36 × 109 /L (32.5% of neutrophils, 30.5% of lymphocytes, and 28.4% of activated lymhocytes), platelets 121 × 109 /L, aspartate aminotransferase (AST) 321 UI/L, alanine aminotransferase (ALT) 214 UI/L, alkaline phosphatase (ALP) 165 UI/L, gammaglutamyl transferase (GGT) 64 UI/L, total bilirubin 20 mol/L, lactate dehydrogenase (LDH) 1838 UI/L. At day 1 of the admission, the first abdominal ultrasonography performed was normal. Serology for EBV showed positive anti-EBV VCA IgM and anti-EBV VCA IgG and negative anti-EBV EBNA IgG confirming primary EBV infection. Search for heterophile antibodies was positive. Two days later, the right upper quadrant abdominal pain increased with a Murphy’s sign at physical examination. Laboratory
174
A. Gagneux-Brunon et al. / Journal of Clinical Virology 61 (2014) 173–175
her admission. Liver enzymes remained increased for two months after admission, and white blood cells count return to normal after three months. Fatigue disappeared after three weeks.
3. Other similar and contrasting cases in the literature
Fig. 1. Gallbladder wall thickening and microabcess in the context of acalculous cholecystitis due to EBV primary infection (Case 1).
findings showed a similar degree of liver enzyme levels compared to admission. A second abdominal ultrasonography showed a striated thickened gall bladder wall (12 mm) with micro-abscesses without lithiasis, suggesting an acute acalculous cholecystitis (see Fig. 1). Intravenous rehydration therapy and antibiotic treatment with ceftriaxone 2 g by day and metronidazole (1500 mg a day) were started due to the risk of perforation of the gallbladder. Digestive surgeons temporized a surgical intervention but examined the patient every day until discharge. At day 7, the abdominal pain disappeared and gallbladder appeared normal at abdominal ultrasonography. Antibiotic therapy was stopped, and the patient was discharged on the eighth day following admission. At day 35, a new ultrasonography and laboratory findings were normal. 2.2. Case 2 A previously healthy Caucasian, 20 year-old woman was admitted with a right quadrant abdominal pain, 7 days after a tonsillopharyngitis to the general surgery department of our institution. On admission, physical examination revealed: moderate jaundice, fever, 38.5 ◦ C, blood pressure, 114/65 mmHg, pulse rate 98/min, respiration rate 18/min, only cervical lymph nodes were enlarged but not inflammatory, tonsil and pharynx were normal, neurological examination was normal. On examination of the abdomen, the right upper quadrant was tender and painful. Spleen and liver were not enlarged. Laboratory findings showed a white blood cells count of 11.52 × 109 /L (14.2% of neutrophils, 41.6% of lymphocytes, and 38.1% of activated lymhocytes), platelets 139 × 109 /L, aspartate aminotransferase (AST) 453 UI/L, alanine aminotransferase (ALT) 494 UI/L, alkaline phosphatase (ALP) 133 UI/L, gammaglutamyl transferase (GGT) 286 UI/L, total bilirubin 38.2 mol/L. An abdominal ultrasonography was performed on the day of the admission, showed an enlarged gallbladder with a gallbladder wall thickened (16 mm) without calculus. In this context, surgeons did not perform a cholecystectomy. An empirical antibiotic treatment was started with amoxicillin and clavulanate (3 g by day). Serologies for cytomegalovirus, HIV, Hepatitis A, B, C, HSV were negative. Serology for EBV revealed that IgG and IgM anti-VCA were positive while IgG anti-EBNA were negative confirming a EBV primary infection, search for heterophile antibodies was positive. Serology for VZV was in favor of an anterior infection. Antibiotics were stopped after the result of EBV serology. Four days later, the abdominal ultrasonography was normal. The patient was discharged 5 days after
In the review that we performed, only 16 other cases were retrieved in PUBMED database showing the rarity of this complication in EBV primary infection [5–17] (Table 1). Acute acalculous cholecystitis contributes to 5–10% of overall cholecystitis. It is usually described in patients with severe trauma and burns, critical illness, cardiovascular surgery [4] and autoimmune disease as lupus. In intensive care, mortality of AAC is high as 40–60%, and surgery is always required [18]. AAC has also been reported during several infectious diseases such as cytomegalovirus primary infection, viral hepatits A, Dengue, infection secondary to non tuberculous mycobacteria, Salmonella spp, leptospirosis, Q-fever, Candida and Malaria [19]. EBV is known to induce elevation of transaminases and jaundice but few data support its association with cholecystitis. Our two cases were very similar to those described in literature. Therefore, the initial clinical presentation (particularly for the first case) was not classical of IM. Table 1 summarized the 16 cases of AAC in the context of EBV primary infection that we found in literature. As highlighted, most of the cases of AAC during EBV primary infection occurred in women (sex ratio 1/16). All the patients were younger than 25 years but only six cases occurred in children under 12 years old (Table 1). This observation may confirm that severe manifestations of EBV primary infection principally occurred in young adults. Patients developing acute acalculous cholecystitis had strong elevation in liver enzymes (Table 1), compared to patients with classical IM, obtained from a series of 114 patients with classical IM [20] (mean AST 515 vs 76.2 UI/L and ALT 552 vs 94.1 UI/L, bilirubin 5.5 vs 0.8 mg/dL). AAC due to EBV primary infection occurred in patients with the highest increase in liver enzymes level. The mechanism of AAC in EBV primary infection is unknown. Most of the authors hypothesized that EBV-induced hepatitis is a cause of cholestasis, inducing gallbladder inflammation and AAC. In the rare AAC reported in children, two of them occurred in children with a Gilbert’s syndrome (GS) [14]. The presence of GS could play a role in the development of gallbladder abnormalities as it is associated with an increase in bilirubin, and since higher level of bilirubin may contribute to AAC in EBV-primary infection. Only one described case had a normal level of bilirubin. In most cases, AAC developed early during the course of the EBV primary infection, 5–7 days after the first clinical signs of IM. In all the cases reported, AAC secondary to EBV primary infection had favorable outcomes. In a majority of cases, antibiotics were prescribed and discontinued after the diagnosis of EBV primary infection was performed. The favorable outcomes of these cases support this attitude. While, AAC is considered as a surgical emergency in critically ill patients, in the case of AAC associated with EBV primary infection, surgical intervention is rarely necessary. In fact in the 16 cases described in Table 1, cholecystectomy was only required in one case, a 22-year old woman, receiving azathioprine for an inflammatory bowel disease [13]. Radiologists first described gallbladder wall thickening in EBV primary infection and proposed it as a sign of severity of infectious mononucleosis [3]. Although EBV primary infections are rarely severe, AAC may cause gallbladder perforation. In conclusion, physicians and digestive surgeons should therefore be aware of the occurrence of AAC during EBV primary infection. When confronted by young patient without past history and presenting an AAC, EBV serology should be performed. Abdominal ultrasonography is also useful in young adults presenting with
No fever Fever, malaise Fever, malaise, pharyngitis
Sore throat, malaise Painful swelling Fever, malaise Fever, malaise, vomiting
Sore throat Sore throat, malaise
Fever, malaise, vomiting Fever, nausea Fever, sore throat Fever, malaise Fever, malaise
None. Competing interests None.
3 7 7
2.5 1.3 4.6
0.9 2.2 300 286
145 103 143 157 133
239 161 434
10 12
+ +
No Yes 48 h No Yes Yes Yes 48 h
5 7 7 5 Yes 24 h
+ + NR NR 5 14 15 0.7 727
299 70 464 166 496 3324 228 494 171 105 329 121 569 3398 244 453
202
2 7 6 8 4.2 4.7 6.5 1.8 584 257
388 220
426 207
156 333
710 919
13.6 9 9 7 9 674 304 179 423 328 394 188
352 241 184 301 142
721 236 629 752 312
4 4.6 4.6 2.9 7
Yes No
Yes Yes Yes 48 h
NR NR NR NR NR NR NR
6 7 1
Yes +
5
Not appropriate, published with the consent of the two patients.
13 4 9 4 18 14 22 22 5 22 20 22 22 29 8 7 18 20 Prassouli et al. [5] Lagona et al. [6] Gora-Gebka et al. [7] Gora-Gebka et al. [7] Iaria et al. [8] Pelliccia et al. [9] Chalupa et al. [10] Cholongitas et al. [11] Attilakos et al. [12] Hagel et al. [13] Yang et al. [14] Dylewski [15] Carrascosa et al. [16] Beltrame et al. [17] Teke et al. [21] Poddighe et al. [22] Case 1 Case 2
F F F F F F F F M F F F F F F F F F
Initial clinical signs before AAC diagnosis Time since the first clinical signs of IM (days) Antibiotics Heterophile ab GWT (mm) Bilirubin (mg/dL) ALP (UI/L) ␥GGT (UI/L) ALT (UI/L) AST (UI/L)
Funding
Ethical approval
Age
Sex
175
right quadrant abdominal pain in the context of EBV primary infection, with a strong elevation in liver enzymes level to confirm AAC. Thanks to this review we could conclude that management of AAC during EBV primary infection require surveillance, and no surgery.
Authors
Table 1 Clinical characteristics and laboratory findings in the 14 described cases of AAC due to EBV primary infection (upper limit values for AST 45 UI/L, ALT 45 UI/L, 80 UI/L for ALP, total bilirubin 10 mg/l, gamma GT 55 UI/L, ab: antibodies, NR: not reported).
A. Gagneux-Brunon et al. / Journal of Clinical Virology 61 (2014) 173–175
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