Viruses | Free Full-Text | Acalculous Cholecystitis as a Complication of Primary Epstein-Barr Virus Infection: A Case-Based Scoping Review of the Literature

By inergency On Mar 18, 2024

3.1. Materials and Methods

Acute acalculous cholecystitis (AAC) during primary EBV infection is an exceedingly rare complication. To better understand the prevalence and clinical characteristics of this condition, a comprehensive literature review was conducted using the PubMed database. The specific queries employed were “acute acalculous cholecystitis” OR “Cholecystitis” AND “Epstein-Barr virus” OR “EBV”, targeting studies that explicitly discussed AAC in the setting of primary EBV infection. Our inclusion criteria were as follows: (1) patients of any age diagnosed with AAC in the context of primary EBV infection, where the diagnosis was supported by serological evidence indicative of recent infection; (2) reports that included case descriptions detailing clinical presentation, diagnosis, and management of AAC during primary EBV infection; (3) articles identified as case reports, case series, and review articles focusing on clinical cases; and (4) articles published in English. We excluded (1) studies not involving AAC associated with primary EBV infection; (2) reports without full case descriptions (e.g., abstracts or articles without full text availability); and (3) literature reviews.

Our strategy yielded 50 published clinical cases, with the most recent one reported in December 2023. The different phases of this review are diagrammatically represented in Figure 1 as a PRISMA flowchart. Extracted data included (1) patient demographics (e.g., age and sex) and study characteristics (e.g., type of study, country of origin); (2) clinical presentation, including cardinal symptoms of EBV and laboratory findings; (3) management strategies, including medical and surgical interventions; and (4) reporting of Gilbert syndrome and the presence of ascites. In Table 2, we provide a summary of our findings. Descriptive statistics were subsequently employed to present them in a narrative manner.

To evaluate the methodological quality of the selected studies and verify causality between EBV and AAC in the reported cases, we applied the appropriate parts of the quality assessment tool suggested by Murad et al. for case reports/series [8]. This tool assesses several key domains—selection of patient/clinical case, ascertainment of exposure and outcomes, exclusion of alternative causes, follow-up, and reporting details—with specific leading questions guiding evaluation. A detailed description of the methodology employed can be found in Table S1 (Supplementary Materials). Overall, two case reports were excluded for the following reasons: one was related to gallbladder wall-thickening, which did not directly pertain to the primary focus of our study; and another presented an alternative plausible cause for ACC, namely scrub typhus. Every other study included in our review met all of the standards described (Table S2, Supplementary Materials).

Table 2.
Summary of key characteristics and laboratory findings in published cases of acute acalculous cholecystitis during primary EBV infection.

Authors	Study Design	Country	Age/Sex	Fever	Cervical Lymphadenopathy	Tonsilitis/ Pharyngitis	Spleno-Megaly	AST/ALT/ALP/GGT	Total Bilirubin (Direct)	Ascites	Gilbert Syndrome	Antibiotic Treatment	Surgery
Fretzayas A. et al. [4]	Case-series	Greece	11/Female	+	+	+	+	291/198/536/52	1.80 (0.4)	N/R	+	−	−
Fretzayas A. et al. [4]	Case-series	Greece	12/Female	+	−	−	+	134/125//162	Normal range	N/R	N/R	−	−
Beltrame V. et al. [9]	Case report	Italy	29/Male	+	+	N/R	N/R	121/166/161/145	1.36 (0.73)	N/R	N/R	+	−
Attilakos A. et al. [10]	Case report	Greece	5/Male	+	+	+	+	207/257/919/333	1.8 (0.9)	N/R	+	−	−
Arya S.O. et al. [11]	Case report	USA	16/Female	+	+	+	−	126/39/409/173	2.5 (1.4)	N/R	N/R	+	−
Suga K. et al. [12]	Case report	Japan	6/Female	+	+	+	−	284/139/506/36	0.4 (0.1)	N/R	N/R	−	−
Gagneux-Brunon A. et al. [13]	Case report	France	18/Female	+	−	−	−	321/214/165/64	1.17 (N/R)	N/R	N/R	+	−
Gagneux-Brunon A. et al. [13]	Case report	France	20/Female	+	+	+	−	453/494/133/286	2.23 (N/R)	N/R	N/R	+	−
Iaria C. et al. [14]	Case report	Italy	18/Female	+	+	+	−	220/328/312/142	7.0 (4.26)	N/R	N/R	+	−
Prassouli A. et al. [15]	Case report	Greece	13/Female	+	N/R	+	−	394/674/721/352	4 (3.5)	N/R	N/R	+	−
Cholongitas E. et al. [16]	Case report	Greece	19/Female	+	+	+	−	426/584/710/156	6.5 (5.17)	N/R	N/R	−	−
Lagona E. et al. [17]	Case report	Greece	4/Female	+	+	+	+	188/304/236/241	4.6 (3.6)	N/R	N/R	−	−
Ono S. et al [18]	Case report	Japan	33/Female	+	+	+	−	225/263/1591/174	1.21 (N/R)	N/R	N/R	+	−
Majdalani M. et al. [19]	Case report	Lebanon	16/Female	+	−	−	+	163/136/625/218	2.5 (2.1)	N/R	N/R	+	−
Koufakis T. et al. [20]	Case report	Greece	21/Male	+	−	−	−	172/232/179/350	6.31 (4.96)	N/R	N/R	−	−
Rodà D. et al. [21]	Case report	Spain	2/Male	+	+	+	+	157/501/800/433	N/R	+	N/R	+	−
Branco L. et al. [22]	Case report	Portugal	16/Female	+	+	+	−	340/689/224/271	0.7 (0.3)	N/R	N/R	+	−
Pawłowska-Kamieniak A. et al. [23]	Case report	Poland	17/Female	+	−	+	−	230/268/311/135	2.2 (N/R)	N/R	N/R	+	−
Alkhoury F. et al. [24]	Case report	USA	15/Female	+	−	−	−	191/221/221/(N/R)	1.8 (1.5)	+	N/R	−	−
Agergaard J. et al. [25]	Case report	Denmark	34/Female	+	−	+	−	(N/R)/61/737/42	N/R	N/R	N/R	+	−
Koch A. D. et al. [26]	Case report	Netherlands	53/Female	+	N/R	N/R	N/R	422/339/1081/(N/R)	7.02 (N/R)	N/R	N/R	−	−
Yang H. N. et al. [27]	Case report	Korea	20/Female	+	+	+	+	171/299/727/202	0.7 (N/R)	N/R	N/R	+	−
Rezkallah KN. et al. [28]	Case report	USA	25/Female	+	−	−	−	94/116/154/(N/R)	N/R (0.5)	N/R	N/R	−	+
Yoshie K. et al. [29]	Case report	Japan	15/Female	+	+	+	+	147/215/569/(N/R)	N/R	N/R	N/R	−	−
Pelliccia P. et al. [30]	Case report	Italy	14/Female	+	+	+	+	137/108/353/ (N/R)	N/R	+	N/R	−	−
Hagel S. et al [31]	Case report	Germany	21/Female	+	N/R	N/R	+	N/R	2.51 (N/R)	N/R	N/R	+	+
Nagdev A. et al. [32]	Case report	USA	18/Female	+	N/R	−	N/R	118/(N/R)/146/(N/R)	1.2 (0.6)	N/R	N/R	+	−
Carrascosa MF. et al. [33]	Case report	Spain	22/Female	+	+	N/R	+	329/464/239/(N/R)	2.49 (2.39)	+	N/R	−	−
Strehle E. et al. [34]	Case report	UK	14/Female	+	N/R	N/R	N/R	207/(N/R)/178/111	N/R (2.34)	N/R	N/R	+	−
Sheybani F. et al. [35]	Case report	Iran	23/Female	+	+	+	+	169/641/909/(N/R)	2.3 (1.1)	+	N/R	−	−
Yesilbag Z. et al. [36]	Case report	Turkey	30/Female	+	N/R	−	+	233/220/376/471	15.4 (14.5)	N/R	N/R	+	−
Cameron A. et al. [37]	Case report	Canada	18/Female	+	+	+	N/R	461/671/258/(N/R)	2.05 (N/R)	N/R	N/R	−	−
Höhn P. et al. [38]	Case report	Germany	24/Male	+	+	N/R	−	116/185/437/258	N/R	N/R	N/R	−	−
Boninsegna S. et al. [39]	Case report	Italy	24/Female	+	N/R	N/R	+	919/914/(N/R)/(N/R)	4.4 (3)	N/R	N/R	+	−
Young C. et al. [40]	Case	USA	14/Female	+	−	−	−	22/13/(N/R)/(N/R)	0.2 (N/R)	N/R	N/R	+	−
Ntelis K. et al. [41].	report	Greece	15/Female	+	+	+	+	106/217/421/177	0.84 (0.32)	N/R	N/R	+	−
Suda T. et al. [42]	Case report	Japan	34/Female	+	+	+	+	368/450/620/275	2.1 (N/R)	N/R	N/R	−	−
Langenohl R. et al. [43].	Case report	USA	3/Male	+	+	N/R	+	259/247/(N/R)/(N/R)	4.3 (N/R)	+	N/R	+	−
Leganés Villanueva C. et al. [44].	Case report	Spain	10/Female	+	+	+	+	279/301/642/297	29 (10)	N/R	N/R	−	−
Nakagawa H. et al. [45].	Case report	Japan	20/Female	N/R	+	+	+	201/190/433/132	N/R	N/R	N/R	−	−
Harvey KG. et al. [46].	Case report	USA	17/Female	N/R	N/R	+	+	105/80/174/(N/R)	4.8 (N/R)	N/R	N/R	−	−
Rein J. et al. [47]	Case report	USA	7/Female	+	+	N/R	+	(N/R)/114/(N/R)/(N/R)	1.8 (1.1)	N/R	N/R	+	−
Avcu G. et al. [48]	Case report	Turkey	15/Female	+	−	+	+	178/268/233/203	2.5 (1.96)	N/R	N/R	+	−
Celik F. et al. [49]	Case report	Turkey	48/Female	+	+	N/R	N/R	221/165/516/224	14.43 (12.9)	N/R	N/R	+	−
Teopoulos Lamprianidis K. et al. [50].	Case report	UK	20/Female	+	+	+	+	(N/R)/247/840/(N/R)	6.8 (N/R)	+	N/R	−	−
Barkho F. et al. [51].	Case Report	USA	19/Male	+	+	N/R	+	150/218/121/(N/R)	3.2 (N/R)	N/R	N/R	−	−
Trbojević T. et al. [52]	Case Report	Croatia	5/Female	−	N/R	−	+	1908/3222/385/51	4.89 (4.0)	N/R	(Family history negative)	−	−
Teles H. et al. [53]	Case Report	Portugal	10/Female	+	+	+	N/R	240/31/(N/R)/(N/R)	N/R	N/R	N/R	+	−
Khan U et al. [54].	Case Report	Norway	Late teens/Female	N/R	N/R	+	N/R	(N/R)/416/218/256	0.8 (0.7)	N/R	N/R	+	−
Present case	Case report	Greece	28/Female	+	+	+	+	468/423/667/423	2.8 (2.4)	+	+	+	−

3.2. Results

This comprehensive literature review, encompassing 50 reported cases (including the one reported in this article), offers insights into the clinical and laboratory characteristics of acalculous cholecystitis in the context of EBV infection, as well as the outcomes of affected patients.

In this review, a marked gender discrepancy was evident: a significant majority of the cases involved females (44/50). The age of the individuals in the reviewed cases ranged from 2 to 53 years, demonstrating that acalculous cholecystitis associated with EBV infection can manifest across a broad age spectrum. However, the median age of 17 years suggests a predominance in adolescents and young adults. Interestingly, our patient was heterozygous for the UGT1A1 gene mutation. Gilbert syndrome was explicitly identified in three cases, with one additional report noting a negative family history for the syndrome. This observation suggests a low reported prevalence of Gilbert syndrome among the reported cases, which may influence the clinical interpretation of bilirubin levels and warrants careful consideration in the management of AAC in the context of EBV infection. AAC is a very rare complication, with the majority of recently described cases occurring in Caucasians, primarily from southern Europe (France, Greece and Italy). Notably, reports from Greece accounted for nine cases, while five case reports were sourced from Italy. This observation could be correlated with the increased incidence of Gilbert syndrome (GS) in the Italian and Greek populations (16.9% and 18.6% respectively) [55]. Attilakos et al. [10] reported a possible correlation between the occurrence of AAC and GS in children with infectious mononucleosis due to EBV. This phenomenon could be explained through the decreased hepatic glucuronidase activity observed in GS patients, which contributes to cholestasis during the course of EBV infection [55].

In terms of clinical manifestations, our review demonstrated that fever was the predominant symptom, observed in nearly all cases that reported its occurrence (46/47). Cervical lymphadenopathy and tonsillitis/pharyngitis were also common, documented in 30/40 and 28/39 cases that provided information on these symptoms, respectively. Conversely, splenomegaly was identified in approximately 60% of the cases (26/42) that noted its occurrence, suggesting that the absence of this condition should not automatically exclude the possibility of this complication. The current case, involving an 18-year-old female, aligns closely with the trends observed in the literature. The patient presented with fever, cervical lymphadenopathy, tonsillitis/pharyngitis, and splenomegaly, features commonly observed in the reviewed cases. A significant difference in our patient’s case was the simultaneous development of ascites during the course of the illness. There are limited reports describing patients with ascites during EBV mononucleosis, and those that do exist describe specific patient types such as immunosuppressed children with primary EBV infection [56], very young children [21], and children with combined EBV and CMV infection [57]. Ascites was less commonly reported in literature, occurring in only eight other cases. Although these symptoms often align with the general symptomatology of EBV infections, their pattern indicates a predisposition for severe disease manifestations, potentially leading to complications such as acalculous cholecystitis. Our case is unique since it describes both acalculous cholecystitis and ascites during the course of a primary EBV infection in an adult individual, where the ascites was not associated with hypoproteinemia. The presence of these two less frequent features adds complexity to the clinical management required and might suggest a more severe disease course.

Laboratory findings further corroborated the hepatic involvement commonly seen in severe EBV infections. Significant hepatic involvement was noted in the majority of cases, with wide variability in AST, ALT, ALP, and GGT levels, indicative of a mixed pattern of hepatocellular injury and cholestasis. Bilirubin levels also varied among reported cases. In 26/43 cases that provided information on bilirubin laboratory parameters, the total bilirubin level was over 2 mg/dL, indicating significant hyperbilirubinemia in more than half of the reported cases.

Antibiotics were administered in the majority of cases (27/50), reflecting either the suspected presence of secondary infection or a precautionary measure against potential bacterial superinfection, while surgery was noted to be a rare intervention, with only two cases undergoing surgical treatment, emphasizing the general approach of conservative management in AAC associated with EBV infection.

Overall, our review findings highlight AAC as a significant but rare complication of primary EBV infection, with a global incidence and a female predominance. The clinical presentation is diverse, with the classic triad of cardinal symptoms, e.g., fever, cervical lymphadenopathy, and tonsillitis/pharyngitis being very common. Correlation with Gilbert’s syndrome could not be established. Laboratory findings reveal significant liver involvement, with varying degrees of enzyme elevations and sometimes hyperbilirubinemia. Finally, the management largely leans conservative, with antibiotics being the mainstay of treatment.

Despite the comprehensive nature of our review in elucidating the prevalence and clinical characteristics of AAC during primary EBV infection, some limitations warrant mention. First, the reliance on published case reports and series inherently limits the generalizability of our findings, as these types of studies may be subject to publication and reporting bias, where only cases with unusual presentations or outcomes are reported. This selective publication and reporting could skew our understanding towards more dramatic manifestations of acute acalculous cholecystitis (AAC) in the context of primary Epstein-Barr virus (EBV) infection, potentially misrepresenting its true clinical spectrum. Lastly, the lack of longitudinal follow-up in many case reports limits insights into long-term outcomes and the potential for recurrent episodes of AAC in patients with primary EBV infection.