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World J Gastroenterol. Nov 21, 2018; 24(43): 4870-4879
Published online Nov 21, 2018. doi: 10.3748/wjg.v24.i43.4870
Acute acalculous cholecystitis in children
Dimitri Poddighe, Vitaliy Sazonov, Department of Medicine, School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan
Vitaliy Sazonov, Pediatric Intensive Care Unit, UMC National Research Center for Mother and Child Health, Astana 010000, Kazakhstan
ORCID number: Dimitri Poddighe (0000-0001-6431-9334); Vitaliy Sazonov (0000-0003-0437-4694).
Author contributions: Poddighe D conceived and wrote the manuscript; Sazonov V contributed to the literature research and data collection.
Conflict-of-interest statement: The authors have no conflict of interest to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dimitri Poddighe, MD, MSc, Assistant Professor, Department of Medicine, School of Medicine, Nazarbayev University, Kerei-Zhanibek Str. 5/1, Astana 010000, Kazakhstan. dimitri.poddighe@nu.edu.kz
Telephone: +7-700-2679413
Received: September 12, 2018
Peer-review started: September 12, 2018
First decision: October 8, 2018
Revised: October 11, 2018
Accepted: October 21, 2018
Article in press: October 21, 2018
Published online: November 21, 2018

Abstract

Acute acalculous cholecystitis (AAC) is the inflammatory disease of the gallbladder in the absence of gallstones. AAC is estimated to represent at least 50% to 70% of all cases of acute cholecystitis during childhood. Although this pathology was originally described in critically ill or post-surgical patients, most pediatric cases have been observed during several infectious diseases. In addition to cases caused by bacterial and parasitic infections, most pediatric reports after 2000 described children developing AAC during viral illnesses (such as Epstein-Barr virus and hepatitis A virus infections). Moreover, some pediatric cases have been associated with several underlying chronic diseases and, in particular, with immune-mediated disorders. Here, we review the epidemiological aspects of pediatric AAC, and we discuss etiology, pathophysiology and clinical management, according to the cases reported in the medical literature.

Key Words: Acute acalculous cholecystitis, Children, Viral biliary disorders

Core tip: Acute acalculous cholecystitis (AAC) is the most frequent form of acute cholecystitis in children. In childhood, this disease has been described in critically ill or post-surgical patients, as it often occurs in adults, but most pediatric cases are actually caused by infectious diseases. In addition to bacterial and parasitic infections, most recent pediatric reports have described children developing AAC during viral illnesses, in particular, Epstein-Barr virus and hepatitis A virus infections. Moreover, some pediatric cases have been associated with non-infectious disorders, such as immune-mediated disorders. Therefore, the medical management presents significant differences compared to adult AAC.



INTRODUCTION

Acute cholecystitis is an inflammatory condition of the gallbladder, which is most commonly associated with the presence of gallstones. These cases are referred to as acute calculous cholecystitis (ACC); here, the obstruction of the cystic duct from small- and medium-sized gallstones that migrate from the gallbladder or from large gallstones that intermittently obstruct the neck of the gallbladder, is considered the main pathogenic moment. However, several clinical and experimental evidences from human and animal studies strongly suggest that biliary obstruction due to gallstones represents only the final event of a more complex pathological process, where the development of acute inflammation is due to the progression from an underlying chronic injury. Very briefly, cholecystitis can develop in the presence of lithogenic bile with high cholesterol concentrations, diffusing through the gallbladder wall and permitting the hydrophobic bile salts to increase the levels of oxidative stress and to trigger the inflammatory process[1,2].

These pathogenic mechanisms may be implicated even in some cases of acute AAC where no gallstones can be identified, but only gallbladder bile sludge. However, most cases of AAC are not associated with any pre-existing biliary disease and/or factors suggesting the presence of lithogenic bile, especially in the pediatric population. Indeed, AAC is the most frequent form of acute cholecystitis in children, whereas in adults it accounts for only 5%-10% of all cases. AAC is estimated to represent at least 50% to 70% of all cases of acute cholecystitis during childhood; of course, the remaining portion is represented by ACC, which is usually associated with hemolytic diseases or intestinal diseases that affect the entero-hepatic recirculation of biliary salts[3,4].

AAC can develop in a variety of clinical settings, suggesting the existence of several pathogenic mechanisms, which may have different weights according to the specific situation. However, those mechanisms can be traced back to two main types of gallbladder injury. One is the chemical injury from bile stasis; however, unlike ACC, the harmful effect on the gallbladder in AAC actually derives from impaired gallbladder emptying rather than altered bile composition[5]. This is likely to be the main trigger in pediatric AAC cases due to some parasite infections obstructing the common bile duct (e.g., Ascaris lumbricoides infestation) or in rare congenital malformations of the gallbladder (e.g., multiseptated gallbladder, diaphragm of the gallbladder, choledochal cyst, etc). Moreover, bile stasis may be also a pathogenic component of AAC in children admitted to the pediatric intensive care unit (PICU) for different reasons. Indeed, the prolonged period of fasting (with oral feeding replaced by parenteral nutrition) and the use of opiates (inducing spasms and/or dyskinesia of the sphincter of Oddi) interferes with gallbladder emptying[6].

A second important mechanism of gallbladder injury is local ischemia[5,6]. The cystic artery is the chief source of blood supply to the gallbladder, in addition to the cystic duct, common hepatic duct and the upper part of the bile duct. The cystic artery can have different anatomical origins, but it usually arises from the right hepatic artery, which is one of the terminal branches of the proper hepatic artery[7]. Importantly, the cystic artery is a terminal artery, meaning that it is the only supply of oxygenated blood to gallbladder tissues, which explains its major susceptibility to ischemic conditions in the presence of several underlying or concomitant diseases. The remarkable importance of the ischemic mechanism in AAC was demonstrated through a fundamental study by Hakala et al[8], published in 1997. Briefly, these authors compared angiographic and histological aspects of patients affected with ACC and AAC. The main gallbladder micro-angiographic findings in AAC were clearly different from those in gallstone-associated cholecystitis. The latter revealed a florid and dilated microcirculation (related to inflammation), whereas an irregular arterial/capillary network with absent or minimal venous filling characterized AAC. Importantly, AAC patients presented quite different underlying diseases (cardiac infarction - treated with emergency coronary bypass -, staphylococcal septicemia, septic shock and hypovolemic shock), which highlighted the fact that ischemic factors and/or tissue hypoxia are the common and final pathogenic mechanisms of gallbladder injury. Further studies confirmed these pathological aspects, and they likely have a prominent role even in AAC cases arising outside the PICU, like patients suffering from vasculitis or previously healthy children developing ACC during a concomitant infectious disease[9,10].

EPIDEMIOLOGY AND RISK FACTORS

Gallbladder disease is a relatively rare condition in children. Before 2000s, Tsakayannis et al[3] estimated only 1.3 pediatric cases for every 1000 cases of adult gallbladder disease. Nevertheless, the incidence of cholecystitis in children has increased over the last 20 years. For example, a recent study from Canada reported that the incidence of pediatric cholecystectomy increased from 8.8 to 13.0 per 100000 person-years from 1993 to 2012, and cholecystitis accounted for 9.3% of all pediatric procedures of the biliary tract[4].

As previously mentioned, AAC represents the most common form of cholecystitis in children (50%-70%), and it can arise in different clinical settings. According to this observation, AAC can be grouped into three main categories: (1) AAC associated with critical medical conditions, (2) AAC associated with underlying (non-critical) diseases, and (3) AAC arising in previously healthy children.

Acute acalculous cholecystitis in children with critical medical conditions

AAC has been described as a complication of several types of surgery. In adults, most reports of post-operative AAC followed interventions of open abdominal aortic reconstruction and cardiac surgery (in particular, cardiac valve replacement with or without bypass)[5]. Of course, this is a very rare occurrence in childhood. Here, the development of AAC related to critical diseases is mostly due to medical conditions requiring prolonged or long-term parenteral feeding, extensive burns and shock syndromes (regardless of the hypovolemic or septic mechanism)[3]. Indeed, those situations are associated with bile stasis and gallbladder ischemia. Moreover, the concomitance and/or the superimposition of infectious factors might contribute to AAC pathogenesis. Finally, Imamoglu et al[11] reported several children developing AAC after appendectomy and blunt abdominal trauma, supporting a mechanism of direct traumatic injury in some pediatric cases. Anyway, post-traumatic AAC in children is very rare, and concomitant factors, such as shock or other comorbidities, may play a role[12].

Acute acalculous cholecystitis in children with non-critical medical conditions

This category includes those cases of AAC developing in patients with comorbidity, which is supposed to contribute to the occurrence of gallbladder disease. Indeed, there are many reports of AAC arising in the context of autoimmune/immune-mediated diseases, in particular vasculitis. Here, the systemic inflammation could also involve the gallbladder vasculature, leading to local ischemic injury[5]. In Table 1, we listed all of the case reports describing AAC in children affected with immune-mediated diseases since 2000[13-18].

Table 1 Reported cases of non-infectious pediatric acute acalculous cholecystitis associated with immune-mediated disorders (2000-2018).
Ref.Age (yr)SexComorbidityClinical manifestations
Basiratnia et al[13], 200610MSystemic lupus erythematosusRUQ pain, fever, nausea, vomiting
Shin et al[14], 20075MNephrotic syndromeAbdominal pain, vomiting
Mendonca et al[15], 200912FSystemic lupus erythematosusAbdominal pain, anorexia, weight loss, nausea, vomiting
Lee et al[16], 2014N/AN/ASystemic lupus erythematosus (n = 2); nephrotic syndrome (n = 1)N/A (patients were included in a large case series of pediatric AAC)
Sanches et al[17], 201411FJuvenile dermatomyositisRUQ pain, nausea, vomiting
Ozkaya et al[18], 20167MHenoch-Shonlein purpuraAbdominal pain, jaundice
Yi et al[19], 2016N/AN/AKawasaki disease (n = 28)N/A (patients were included in a large case series of pediatric AAC)

Among these immunological conditions, Kawasaki disease received particular attention and detailed description. According to the large case series published by Yi et al[19], which included 131 children with AAC, 26.7% of patients were affected with a systemic (non-infectious) disease, and most had Kawasaki disease (28 cases). Interestingly, these authors found that the presence of AAC in the acute phase of Kawasaki disease was statistically associated with the development of coronary complications, in addition to more severe clinical presentations[20]. Previously, Chen et al[21] studied the occurrence of gallbladder abnormalities (including AAC or hydrops) in children with Kawasaki disease, and they found higher rates of intravenous immunoglobulin resistance.

Additional reports of AAC associated with systemic (non-infectious) illnesses included malignancies (e.g., hemophagocytic lymphohistiocytosis, acute leukemias), renal diseases (e.g., end-stage renal disease) and genetic diseases (e.g., galactosemia, diabetes mellitus, cystic fibrosis)[16,19,22-24].

Acute acalculous cholecystitis in previously healthy children

Most cases of pediatric AAC have been described in children without life-threatening conditions or underlying comorbidities. In this group, a large variety of infectious agents have been implicated in the pathogenesis of AAC, including viruses, bacteria, yeasts and parasites. Before 2000, most reports of infectious AAC referred to intestinal parasites (e.g., Ascaris lumbricoides), typhoid fever and leptospirosis[6]. AAC can be one of the clinical manifestations of hepatobiliary ascariasis, characterized by the passage of worms from the duodenum to the biliary tract, leading to bile flow obstruction[25]. Typhoid fever is a systemic infection caused by some Salmonella species, in particular Salmonella typhi. AAC in typhoid fever is usually a secondary complication depending on bacterial strain virulence or its resistance to treatment, especially in endemic areas. These bacteria reach the gallbladder through the blood stream and have been shown to have a tropism for the vesicular wall epithelium[26]. Leptospirosis is a zoonotic infection sustained by several species of the genus Leptospira and, again, AAC derives from the direct localization of these bacteria in the gallbladder[27].

However, after 2000 (probably due to the larger diffusion of the abdominal ultrasound), a multitude of publications have associated pediatric AAC with many types of infections, including several viral diseases. In Table 2, we listed all case reports or small case series describing infectious AAC in children, in whom a clear etiological diagnosis was achieved[28-60].

Table 2 Reported cases of pediatric acute acalculous cholecystitis associated with specific infections (2000-2018).
Ref.Age (yr)SexComorbidityClinical manifestations
Ashley et al[28], 20004MB. abortusRUQ pain, fever, constipation, anorexia
Ciftci et al[29], 20017MHAVAbdominal pain, fever, jaundice
Lo et al[30], 20025MSalmonella group DAbdominal pain, fever, vomiting, diarrhea
Batra et al[31], 200312MS. aureusRUQ pain, fever, jaundice, maculopapular rash
Garel et al[32], 20034MSalmonella spp.Abdominal pain, fever, vomiting, diarrhea
Saha et al[33], 20057FP. falciparumRUQ pain, fever
Axelrod et al[44], 20073FS. typhiAbdominal pain, fever, vomiting
Kuttiat et al[35], 20078 and 9MP. falciparum and P. vivaxRUQ pain, fever, vomiting (P. vivax)
Lagona et al[36], 20074FEBVRUQ pain, fever, jaundice, vomiting, anorexia
Anthoine-Milhomme et al[37], 20077FPlasmodium spp.Abdominal pain, fever, diarrhea, jaundice
Prassouli et al[38], 200713FEBVAbdominal pain, fever, vomiting, jaundice
Gora-Gebka et al[39], 20089 and 4FEBV + CMV and EBVRUQ pain, fever, jaundice, enlargement of liver and spleen
Kumar et al[40], 20083FP. falciparumAbdominal pain, fever, vomiting
Bouyahia et al[41] 200814MHAVAbdominal pain, vomiting, fever
Attilakos et al[42], 20095MEBVFever, jaundice, enlargement of liver and spleen
Sureshet al[43], 20092FHAVAbdominal pain, fever, vomiting
Souza et al[44], 200916MHAVAbdominal pain, fever, vomiting
Arroud et al[45], 201111MHAVAbdominal pain, fever, vomiting, jaundice
Herek et al[46], 20119MHAVAbdominal pain, fever, vomiting, jaundice
Prashanth et al[47], 201212FHAVAbdominal pain, vomiting
Newcombe et al[48], 20139MC. burnetiiN/A
Gnassingbe et al[49], 20135-134 M, 2 FS. typhiMainly abdominal pain, fever and vomiting
Poddighe et al[50], 20147FEBVRUQ, fever, vomiting, jaundice, liver enlargement.
Kim et al[51], 201410FEBVRUQ pain, fever, cervical lymphadenopathy
Fretzajas et al[52], 201411 and 12FEBVAbdominal pain, fever, jaundice, hepatosplenomegaly
Strehle et al[53], 201414FEBVFever, RUQ pain, vomiting, anorexia, eyelid swelling
Suga K et al[54], 20146FEBVAbdominal pain, epigastralgia
Alkoury et al[55], 201515FEBVAbdominal pain, fever, vomiting
Pawlowska-Kamieniak et al[56], 201517FEBVRUQ pain, fever, anorexia
Majdalani et al[56], 201616FEBVAbdominal pain, fever, vomiting
Gomes et al[58], 20163MHHV-6Abdominal pain, vomiting, generalized maculo-papular skin rash
Ismaili-Jaha et al[59], 20181, 2, 4, 10F, F, F, MAscaris lumbricoidesMainly fever, diarrhea, vomiting
Aguilera-Alonso et al[60], 20185FP. falciparumAbdominal pain, fever, jaundice

Among AAC cases due to viral infections, many have been associated with hepatitis A virus (HAV) and Epstein-Barr virus (EBV); however, only a minority of infected children develop AAC, which represents a rare complication.

As for EBV specifically, Yi et al[61] recently described 94 children affected by primary infection and undergoing abdominal ultrasonography. Around 25% of patients showed gallbladder abnormalities, particularly increased wall thickness; however, only a very small percentage (2%) fulfilled the diagnostic criteria for AAC. Interestingly, the authors noticed that EBV hepatitis seems to be more frequently associated with cholestasis abnormalities (e.g., increase of γ-glutamyl transpeptidase) compared to infections sustained by other herpes viruses (e.g., Cytomegalovirus)[62,63]. Unfortunately, the pathogenic mechanisms of viral AAC are not well known, but direct invasion or inflammation triggered by bile stasis may play a role. As for HAV, direct viral invasion of the gallbladder has been documented by Mourani et al[64] in a dated study. However, the local extension of the hepatic inflammatory process and/or elevated portal pressure (leading to edema of the gallbladder wall) have been speculated by some authors[65].

CLINICAL AND DIAGNOSTIC ASPECTS

In critically ill children who are not able to communicate appropriately, the diagnostic suspicion of AAC often derives from the onset of biochemical abnormalities suggesting cholestasis and liver dysfunction (e.g., plasma bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase), in addition to fever and leukocytosis. Otherwise, the main clinical manifestation of AAC is abdominal pain (mild to severe), typically in the right upper quadrant, but sometimes diffuse. Fever, jaundice, vomiting and nausea can be variably present. Then, the clinical presentation is quite nonspecific, and the diagnosis can be challenging, especially when AAC is superimposed on acute hepatitis, whose laboratory findings can be similar because of concomitant intrahepatic cholestasis[6,66,67].

Therefore, AAC diagnosis necessarily relies on abdominal ultrasonography (US), which can reveal typical findings and diagnostic criteria, as follows: (1) Increased gallbladder wall thickness (> 3.5 mm); (2) pericholecystic fluid; (3) presence of mucosal membrane sludge; and (4) gallbladder distension. The presence of at least two of these US criteria, in addition to the absence of gallstones, usually supports the diagnosis of AAC in the pediatric age[10]. Thickening of the gallbladder wall is the most reliable single criterion, with a specificity of 90% and 98.5% using the cut-off of 3.0 mm and 3.5-mm wall thickness, respectively; moreover, the sensitivity was 100% at 3.0 mm, but only 80% at 3.5 mm. Therefore, especially in the presence of suggestive clinical and laboratory findings, gallbladder wall thickness of 3.5 mm or more by itself is generally accepted to be diagnostic[5,68]. Among other imaging studies of the biliary tract, computerized tomography (CT) has been shown to be as accurate as US in the diagnosis of AAC, but it has some limitations due to radiological exposure, especially in the pediatric age. Moreover, CT is more expensive and cannot be performed bedside. However, CT should be used any time that other thoracic and/or abdominal diagnoses are under consideration and it is essential for the pre-operative assessment, if required (see below). The diagnostic criteria for AAC by CT are similar to those described for US[5,69,70]. Other imaging studies such as technetium-labeled scintigraphy are quite problematic in children and, importantly, could be of limited value in the critical setting because of potential false positive results, due to prolonged fasting and concomitant liver disease[5,71].

THERAPEUTIC MANAGEMENT

AAC therapy in adults is substantially surgical, namely cholecystectomy. Indeed, a substantial rate of complications (e.g., empyema, perforation, gangrene) and the possibility of other underlying biliary diseases (malignancy, for instance) must be considered. Here, open or laparoscopic cholecystectomy provides both the possibility to review the gallbladder and the definitive treatment. Therefore, supportive therapy (e.g., analgesic drugs, intravenous hydration, parenteral nutrition) and antibiotics do not substitute the surgical approach, although they represent an essential part[65,72,73].

However, the epidemiology and etiology of pediatric AAC is quite different from adults, as previously shown. Therefore, even the therapeutic management of AAC in children is different and, in particular, the frequency of the surgical approach is generally much lower than in adults or in children with ACC[6,74]. In Table 3, we reported the conservative or interventional management in all available pediatric reports and small (uniform by etiology) case series[13-15,17,28,30,31,33,35-39,41,43-48,50,51,53-56,75-80]. As already mentioned, this overview confirms that the management of AAC in children is often conservative. Most AAC children who finally required surgical management were affected with vasculitis or systemic bacterial infections or, interestingly, were patients who did not receive a final diagnosis, as the cause of AAC remained unknown.

Table 3 Main therapeutic approach in the reported cases of pediatric acute acalculous cholecystitis (2000-2018).
Author (etiology, yr, country)Age (yr)/sexSurgeryAntibioticObservations
Ashley et al[28] (B. Abortus, 2000, United States)4-M-Cotrimoxazole rifampinDiagnosis through blood culture (initial antibiotic therapy with ampicillin, metronidazole and gentamicin)
Croteau et al[75] (N/A, 2001, United States)2-MLaparoscopic cholecystectomySecond-generation cephalosporinRemoval of gallbladder after AAC recurrence
Lo et al[30] (Salmonella group D, 2002, Taiwan)5-MLaparotomic cholecystectomyCeftriaxoneRemoval of gallbladder for AAC complicated by empyema
Batra et al[31] (S. Aureus, 2003, United States)12-MLaparotomic cholecystectomyAmpicillin/sulbactam Ceftriaxone, metronidazoleAAC developed for bacteriemia during osteomyelitis.
Saha et al[33] (P. Falciparum, 2005, India)7-F-CeftriaxoneIntravenous quinine as soon as definitive diagnosis was achieved
Basiratnia et al[13] (SLE, 2006, Iran)10-MLaparotomic cholecystectomyCeftriaxone, metronidazoleHigh-dose prednisolone for 3 d. Surgical approach due to poor response (not specified)
Kuttiat et al[35] (P. falciparum and P. Vivax, 2007, India)8-M 9-M-CeftriaxoneIntravenous quinine as soon as definitive diagnosis was achieved
Lagona et al[36] (EBV, 2007, Greece)4-F--Only supportive therapy and close follow-up
Anthoine-Milhomme et al[37] (Plasmodium spp., 2007, France/Ivory Coast)7-F-Amoxicillin triamphenicolHalofantrin was started upon diagnosis
Prassouli et al[38] (EBV, 2007, Greece)13-F-Cefotaxime, tobramicin, metronidazole
Shin et al[14] (Nephrotic syndrome, 2007, South Korea)5-M-Ampicillin, cefotaximeDeflazacort 60 mg/m2
Gora-Gebkaet al[39] (EBV + CMV and EBV, 2008, Poland)9-F, 4-F-Cefotaxime
Bouyahia et al[41] (HAV, 2008, Tunisia)14-M-Cefotaxime, gentamicin
Suresh et al[43] (HAV, 2009, India)2-F--
Souza et al[44] (HAV, 2009, Brazil)16-M--
Mendonca et al[15], (SLE, 2009, Brazil)12-F--Concomitant SNC vasculitis findings: treated with high-dose prednisolone for 3 d.
McNaughton et al[76] (N/A, 2010, United States)14-MLaparoscopic cholecystectomyAntibiotics (not specified)
Karkera et al[77] (N/A, 2010, India)11-MLaparotomic cholecystectomyAntibiotics (not specified)Both patients developed complicated (perforated) AAC
Arroud et al[45] (HAV, 2011, Morocco)11-M-Amoxicillin-clavulanic acid, gentamicin
Herek et al[46] (HAV, 2011, Turkey)9-M--
Pal K[24], (Type I Diabetes mellitus, 2011, Saudi Arabia)11-MLaparoscopic cholecystectomyAntibiotics (not specified)Emphysematous AAC associated with secondary appendicitis. Bile bacteriology revealed E. Coli and Ebterococcus spp
Prashanth et al[47] (HAV, 2012, India)12-F--
Newcombe et al[48] (C. Burnetii, 2013, Australia)9-M-Ampicillin, gentamicin, metronidazoleAAC as probable complication of infection-associated anti-phospholipid syndrome
Shihabuddin et al[22] (Cystic fibrosis, 2013, United States)10-F-Antibiotics (not specified)
Poddighe et al[50] (EBV, 2014, Italy)7-F-CefotaximePatient coming from South-East Asia
Kim et al[51] (EBV, 2014, South Korea)10-F-Antibiotics (not specified)
Strehle et al[53] (EBV, 2014, United Kingdom)14-F-Antibiotics (not specified)
Sanches et al[17] (JDM, 2014, Portugal)11-F--high-dose prednisolone for 3 d
Suga et al[54] (EBV, 2014, Japan)6-F--Only supportive therapy
Alkoury et al[55] (EBV, 2015, United States)15-F-N/A
Pawlowska-Kamieniak et al[56] (EBV, 2015, Poland)17-F-Antibiotics (not specified)UDCA, analgesics, and relaxants
Muta et al[78] (N/A, 2015, Japan)6-MLaparoscopic cholecystectomyN/ACase of eosinophilic cholecysitis without evidence of other eosinophilic disease
Majdalani et al[57] (EBV, 2016, Lebanon)16-F-Ciprofloxacin, metronidazole
Rodà et al[79] (EBV, 2016, Spain)2-M-CeftriaxoneConcomitant nephrotic syndrome and EBV infection
Özkaya et al[18] (Henoch-Schonlein purpura, 2016, Turkey)7-MLaparotomic cholecystectomyAntibiotics (not specified)
Gomes et al[58] - (HHV-6, 2016, Portugal)3-M--
Naselli et al[23] (ALL-T, 2017, United Kingdom)12-M-Piperacillin-tazobactam, metronidazoleNeutropenia during chemotherapy (dexamethasone, daunorubicin, vincristine, PEG-asparaginase)
Aguilera-Alonso et al[60] (Plasmodium falciparum, 2018, Spain/Equatorial Guinea)5-F-Clindamycin, cefotaxime, metronidazoleIntravenous quinine as soon as definitive diagnosis was achieved
Ismaili-Jaha et al[59] (Ascaris lumbricoides, Albania, 2018)1-F, 2-F, 4-F, 10-M-Antibiotics (not specified)Mebendazole
Ng et al[80] (N/A, concomitant pneumonia, 2018, Australia)7-M-Ceftriaxone, metronidazole

In addition to all those case reports, there are some larger and/or heterogeneous case series that deserve to be discussed separately. Imagoglu et al[11] described 12 children that developed AAC after previous abdominal surgery, during severe systemic infections or because of blunted abdominal trauma. Three of them required cholecystectomy because of the deterioration of their clinical conditions and US findings. Previously, in 1975 Ternberg et al[27] reviewed 67 pediatric cases: 36 patients underwent cholecystectomy and 25 patients were treated by tube cholecystostomy; however, no analysis according to the etiology of AAC was provided in this study. Chirdan et al[81] (from Nigeria) and Gnassingbé et al[49] (form Togo) described two small case series of children developing AAC because of S. typhi infection, including sixteen (13 M, 3 F) and six (4 M, 2 F) patients, respectively. Interestingly, almost all children (except one in Chirdan’s study) required cholecystectomy by laparotomy as a final treatment, in addition to antibiotics, which supports the previous observations about the medical management in children.

Unfortunately, very few pediatric case series described AAC in critically ill children, but conservative management is strongly pursued, because these patients may not be able to safely sustain surgical (and anesthesiology) procedures. Huang et al[82] retrospectively described their experience with 109 children with AAC (from 2000 to 2009) due to a variety of etiologies and highlighted some findings (including low platelet count, low hemoglobin value, presence of pericholecystic fluid/high sonographic score, hypofibrinogenemia and septic shock) as being predictive of poor outcome. However, all of their patients were treated non-operatively, including those affected with critical illnesses. They reported 15% mortality rate (16 patients), and most of them (11 patients) developed AAC during sepsis (presented by a total of 27 patients), who then died of shock and multi-organ failure. Of course, it is not possible to make any conclusion about the most correct therapeutic management in these cases, but a timely surgical approach might be considered in selected situations, whenever the clinical condition allows it and before irreversible clinical deterioration. More recently, in a retrospective study (from 2004 to 2014) by Yi et al[19] (including 131 children), only two patients (1.5%) underwent cholecystectomy. Interestingly, no patients were admitted to the intensive care unit or presented with septic shock, but the indication for shifting from the conservative to the surgical approach was not specified. On the contrary, Rijcken[83] performed cholecystectomy in all seven cases he described from his experience in a Malawi hospital, suggesting surgery as a preferential approach “in the African setting” and “in the very ill patient”. Only one child died post-operatively because of complicated sepsis. Recently, Schaefer CM retrospectively described ten critically ill and immune-compromised children who underwent percutaneous cholecystostomy. All patients were admitted to the intensive care unit; four children were hemodynamically unstable, three had multi-organ system failure, three developed renal failure and one was in septic shock. No patient developed procedure-related complications, but four patients died because of concomitant multi-organ failure. The surviving children benefited from percutaneous cholecystostomy, as three of them returned to normal gallbladder function, and this interventional procedure obviated cholecystectomy in the remaining three children until they were in such a clinical condition to endure it[84].

In summary, the current therapeutic management of AAC in children is mostly conservative, but hospital admission should be recommended in order to monitor the clinical and sonographic evolution in any individual case. Indeed, as mentioned previously, the study by Huang et al[82] reported a mortality rate of 15%, and more recently, Lu et al[85] showed that 29.25% of their pediatric patients needed the intensive care unit, and around 9.5% died. Again, concomitant sepsis was the main comorbidity in fatal AAC cases, but also other severe or lethal complications may develop[82,85].

Regardless of the etiology or the clinical condition, supportive therapy (analgesia, rehydration) is mandatory. Moreover, oral feeding is usually suspended until the amelioration in order to avoid stimulation of bile production, and the evacuation of gastric contents via nasogastric tube may be appropriate in some cases. Consequently, intravenous fluid replacement and parenteral nutrition is paramount[5,6]. Importantly, children must receive effective pain relief through nonsteroidal anti-inflammatory drugs, while opiates should be avoided. Finally, considering the frequent implication of infections in the development of AAC, antibiotic therapy should almost always be recommended and should include antibiotics against both gram-negative and anaerobic microorganisms, unless there is a different indication from the clinical situation and/or microbiological results. Antibiotic therapy is often prescribed even in AAC cases with a high suspicion of viral infection in order to prevent further complications, as described in Table 3. Most used antibiotics were a variable combination of a third generation cephalosporin, gentamicin and metronidazole[86,87]. Unfortunately, specific guidelines for pediatric cholecystitis are not available, and controlled studies are necessary to establish the most appropriate medical management of pediatric AAC.

CONCLUSION

AAC is a very heterogeneous disease, as it can arise in multiple clinical settings and can be sustained by different and/or overlapping pathogenic mechanisms. Importantly, the therapeutic management of pediatric AAC significantly differs from adults. Indeed, according to our literature review, most cases in children have been conservatively managed, while the surgical procedure (namely, laparotomic or laparoscopic cholecystectomy) was required in a minority of cases. Importantly, cholecystectomy was mostly performed in children developing AAC due to systemic bacterial infections or with no clear etiology. Indeed, those patients were more prone to complications (e.g., empyema, perforation), which represents the main indication for surgery in children. Most pediatric AAC cases were associated with viral infections (in particular, HAV and EBV), which showed lower rates of complications. In these cases, supportive management (including appropriate rehydration, temporary suspension of oral feeding and analgesic therapy) was sufficient. However, in almost all cases, wide-spectrum antibiotic therapy has been implemented despite the viral etiology. It is not always possible to immediately achieve a conclusive etiologic diagnosis, and that may be the reason why antibiotics are often or initially used. Therefore, in the management of pediatric AAC, pediatricians should be aware that many cases have a good prognosis and are often due to viral illnesses; however, if or until the viral nature is not completely evident, it is still recommended to start an appropriate antibiotic therapy. Moreover, children with AAC should always be admitted to the hospital to provide a tight clinical and sonographic follow-up, which can allow for quick response after complications that require a surgical approach.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Kazakhstan

Peer-review report classification

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Grade B (Very good): B

Grade C (Good): C

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Grade E (Poor): 0

P- Reviewer: Horesh N, Kim JS S- Editor: Wang XJ L- Editor: Filipodia E- Editor: Bian YN

References
1.  Elwood DR. Cholecystitis. Surg Clin North Am. 2008;88:1241-1252, viii.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 75]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
2.  Behar J, Mawe GM, Carey MC. Roles of cholesterol and bile salts in the pathogenesis of gallbladder hypomotility and inflammation: cholecystitis is not caused by cystic duct obstruction. Neurogastroenterol Motil. 2013;25:283-290.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 14]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
3.  Tsakayannis DE, Kozakewich HP, Lillehei CW. Acalculous cholecystitis in children. J Pediatr Surg. 1996;31:127-130; discussion 130-131.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 81]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
4.  Murphy PB, Vogt KN, Winick-Ng J, McClure JA, Welk B, Jones SA. The increasing incidence of gallbladder disease in children: A 20year perspective. J Pediatr Surg. 2016;51:748-752.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 33]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
5.  Barie PS, Eachempati SR. Acute acalculous cholecystitis. Gastroenterol Clin North Am. 2010;39:343-357.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 170]  [Cited by in F6Publishing: 141]  [Article Influence: 10.1]  [Reference Citation Analysis (1)]
6.  Poddighe D, Tresoldi M, Licari A, Marseglia GL. Acalculous Acute Cholecystitis in Previously Healthy Children: General Overview and Analysis of Pediatric Infectious Cases. Int J Hepatol. 2015;2015:459608.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 30]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
7.  Chen WJ, Ying DJ, Liu ZJ, He ZP. Analysis of the arterial supply of the extrahepatic bile ducts and its clinical significance. Clin Anat. 1999;12:245-249.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 3]  [Reference Citation Analysis (0)]
8.  Hakala T, Nuutinen PJ, Ruokonen ET, Alhava E. Microangiopathy in acute acalculous cholecystitis. Br J Surg. 1997;84:1249-1252.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 52]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
9.  Laurila JJ, Ala-Kokko TI, Laurila PA, Saarnio J, Koivukangas V, Syrjälä H, Karttunen TJ. Histopathology of acute acalculous cholecystitis in critically ill patients. Histopathology. 2005;47:485-492.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 46]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
10.  Warren BL. Small vessel occlusion in acute acalculous cholecystitis. Surgery. 1992;111:163-168.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Imamoğlu M, Sarihan H, Sari A, Ahmetoğlu A. Acute acalculous cholecystitis in children: Diagnosis and treatment. J Pediatr Surg. 2002;37:36-39.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 58]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
12.  Meka M, Scorpio R, Bromberg W. Acute acalculous cholecystitis in a pediatric trauma patient. Am Surg. 2008;74:881-882.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Basiratnia M, Vasei M, Bahador A, Ebrahimi E, Derakhshan A. Acute acalculous cholecystitis in a child with systemic lupus erythematosus. Pediatr Nephrol. 2006;21:873-876.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 19]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
14.  Shin YH, Shin JI, Park JM, Kim JH, Lee JS, Kim MJ. A five-year-old boy with nephrotic syndrome complicated with acute acalculous cholecystitis. Pediatr Int. 2007;49:674-676.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 5]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
15.  Mendonça JA, Marques-Neto JF, Prando P, Appenzeller S. Acute acalculous cholecystitis in juvenile systemic lupus erythematosus. Lupus. 2009;18:561-563.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 19]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
16.  Lee JH, No YE, Lee YJ, Hwang JY, Lee JW, Park JH. Acalculous diffuse gallbladder wall thickening in children. Pediatr Gastroenterol Hepatol Nutr. 2014;17:98-103.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 11]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
17.  Sanches BF, Martins T, Santos MJ, Azeredo P. Acute acalculous cholecystitis in a patient with juvenile dermatomyositis. BMJ Case Rep. 2014;2014.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 6]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
18.  Özkaya AK, Güler E, Çetinkaya A, Karakaya AE, Göksügür Y, Katı Ö, Güler AG, Davutoğlu M. Henoch-Schönlein purpura complicated by acalculous cholecystitis and intussusception, and following recurrence with appendicitis. Paediatr Int Child Health. 2016;36:157-159.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 7]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
19.  Yi DY, Chang EJ, Kim JY, Lee EH, Yang HR. Age, Predisposing Diseases, and Ultrasonographic Findings in Determining Clinical Outcome of Acute Acalculous Inflammatory Gallbladder Diseases in Children. J Korean Med Sci. 2016;31:1617-1623.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 12]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
20.  Yi DY, Kim JY, Choi EY, Choi JY, Yang HR. Hepatobiliary risk factors for clinical outcome of Kawasaki disease in children. BMC Pediatr. 2014;14:51.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 25]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
21.  Chen CJ, Huang FC, Tiao MM, Huang YH, Lin LY, Yu HR, Yang KD, Huang YC, Chen CC, Chang WC. Sonographic gallbladder abnormality is associated with intravenous immunoglobulin resistance in Kawasaki disease. ScientificWorldJournal. 2012;2012:485758.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 32]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
22.  Shihabuddin B, Sivitz A. Acute acalculous cholecystitis in a 10-year-old girl with cystic fibrosis. Pediatr Emerg Care. 2013;29:117-121.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 6]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
23.  Naselli A, Bishop H, Walker S, Warris A. Neutropenic acute acalculous cholecystitis (AAC) in a 12-year-old boy with T-acute lymphoblastic leukemia successfully managed with conservative treatment. Pediatr Hematol Oncol. 2017;34:24-28.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 5]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
24.  Pal K. Laparoscopy in the management of emphysematous cholecystitis and secondary appendicitis in an 11-year-old child with insulin-dependent diabetes mellitus. Afr J Paediatr Surg. 2011;8:211-214.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 5]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
25.  Khuroo MS, Rather AA, Khuroo NS, Khuroo MS. Hepatobiliary and pancreatic ascariasis. World J Gastroenterol. 2016;22:7507-7517.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 62]  [Cited by in F6Publishing: 45]  [Article Influence: 5.6]  [Reference Citation Analysis (1)]
26.  Menendez A, Arena ET, Guttman JA, Thorson L, Vallance BA, Vogl W, Finlay BB. Salmonella infection of gallbladder epithelial cells drives local inflammation and injury in a model of acute typhoid fever. J Infect Dis. 2009;200:1703-1713.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 83]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
27.  Ternberg JL, Keating JP. Acute acalculous cholecystitis. Complication of other illnesses in childhood. Arch Surg. 1975;110:543-547.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 69]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
28.  Ashley D, Vade A, Challapalli M. Brucellosis with acute acalculous cholecystitis. Pediatr Infect Dis J. 2000;19:1112-1113.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 14]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
29.  Ciftci AO, Karnak I, Tanyel FC. The association of hepatitis A virus infection, acalculous cholecystitis, and blunt abdominal trauma: a diagnostic challenge. J Pediatr Gastroenterol Nutr. 2001;32:92-94.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 9]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
30.  Lo WT, Wang CC, Chu ML. Acute septicaemic acalculous cholecystitis complicated by empyema caused by Salmonella group D in a previously healthy child. Eur J Pediatr. 2002;161:575-577.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 4]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
31.  Batra V, Ang JY, Asmar BI. Staphylococcal acalculous cholecystitis in a child. South Med J. 2003;96:206-208.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 8]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
32.  Garel L, Lucaya J, Piqueras J. Acute acalculous cholecystitis owing to salmonella sepsis. Pediatr Radiol. 2003;33:905-906.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 8]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
33.  Saha A, Batra P, Vilhekar KY, Chaturvedi P. Acute acalculous cholecystitis in a child with Plasmodium falciparum malaria. Ann Trop Paediatr. 2005;25:141-142.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 13]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
34.  Axelrod D, Karakas SP. Acalculous cholecystitis and abscess as a manifestation of typhoid fever. Pediatr Radiol. 2007;37:237.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 5]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
35.  Kuttiat VS, Kohli U. Acute acalculous cholecystitis associated with malarial infection in children: report of two cases. J Trop Pediatr. 2007;53:59-61.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 8]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
36.  Lagona E, Sharifi F, Voutsioti A, Mavri A, Markouri M, Attilakos A. Epstein-Barr virus infectious mononucleosis associated with acute acalculous cholecystitis. Infection. 2007;35:118-119.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 36]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
37.  Anthoine-Milhomme MC, Chappuy H, Chéron G. Acute acalculous cholecystitis in a child returning from the Ivory Coast. Pediatr Emerg Care. 2007;23:242-243.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 12]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
38.  Prassouli A, Panagiotou J, Vakaki M, Giannatou I, Atilakos A, Garoufi A, Papaevangelou V. Acute acalculous cholecystitis as the initial presentation of primary Epstein-Barr virus infection. J Pediatr Surg. 2007;42:E11-E13.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 29]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
39.  Gora-Gebka M, Liberek A, Bako W, Szarszewski A, Kamińska B, Korzon M. Acute acalculous cholecystitis of viral etiology--a rare condition in children? J Pediatr Surg. 2008;43:e25-e27.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 36]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
40.  Kumar A, Taksande AM, Vilhekar KY. Acalculous cholecystitis by P. falciparum in a 3-year-old child. J Vector Borne Dis. 2008;45:76-77.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Bouyahia O, Khelifi I, Bouafif F, Mazigh Mrad S, Gharsallah L, Boukthir S, Sammoud El Gharbi A. Hepatitis A: a rare cause of acalculous cholecystitis in children. Med Mal Infect. 2008;38:34-35.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 14]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
42.  Attilakos A, Prassouli A, Hadjigeorgiou G, Lagona E, Kitsiou-Tzeli S, Galla A, Stasinopoulou A, Karpathios T. Acute acalculous cholecystitis in children with Epstein-Barr virus infection: a role for Gilbert’s syndrome? Int J Infect Dis. 2009;13:e161-e164.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 26]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
43.  Suresh DR, Srikrishna R, Nanda SK, Annam V, Sunil K, Arjun B. Acalculous gallbladder distension in a young child due to HAV infection: Diagnostic dilemma. Indian J Clin Biochem. 2009;24:316-318.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 8]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
44.  Souza LJ, Braga LC, Rocha Nde S, Tavares RR. Acute acalculous cholecystitis in a teenager with hepatitis a virus infection: a case report. Braz J Infect Dis. 2009;13:74-76.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 18]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
45.  Arroud M, Benmiloud S, Oudghiri B, Afifi MA, Hida M, Bouabdallah Y. Acute acalculous cholecystitis revealing hepatitis A virus infection in children. Saudi J Gastroenterol. 2009;15:277.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 11]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
46.  Herek O, Cördük N, Herek D, Bagci S. Acute acalculous cholecystitis due to hepatitis A infection in a child: a rare cause of acute abdomen. Ann Afr Med. 2011;10:193-195.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 6]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
47.  Prashanth GP, Angadi BH, Joshi SN, Bagalkot PS, Maralihalli MB. Unusual cause of abdominal pain in pediatric emergency medicine. Pediatr Emerg Care. 2012;28:560-561.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 13]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
48.  Newcombe JP, Gray PE, Palasanthiran P, Snelling TL. Q Fever with transient antiphospholipid antibodies associated with cholecystitis and splenic infarction. Pediatr Infect Dis J. 2013;32:415-416.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 11]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
49.  Gnassingbé K, Katakoa G, Kanassoua KK, Adabra K, Mama WA, Simlawo K, Eteh K, Tekou H. Acute cholecystitis from typhic origin in children. Afr J Paediatr Surg. 2013;10:108-111.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 7]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
50.  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.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 22]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
51.  Kim A, Yang HR, Moon JS, Chang JY, Ko JS. Epstein-barr virus infection with acute acalculous cholecystitis. Pediatr Gastroenterol Hepatol Nutr. 2014;17:57-60.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 17]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
52.  Fretzayas A, Moustaki M, Attilakos A, Brozou T, Nicolaidou P. Acalculous cholecystitis or biliary dyskinesia for Epstein-Barr virus gallbladder involvement? Prague Med Rep. 2014;115:67-72.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 11]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
53.  Strehle EM, De Alwis Y, Saleem M. Epstein-Barr virus-associated acute cholecystitis in a teenager. Ultrasound. 2014;22:123-125.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 6]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
54.  Suga K, Shono M, Goji A, Matsuura S, Inoue M, Kawahito M, Mori K. A case of acute acalculous cholecystitis complicated by primary Epstein-Barr virus infection. J Med Invest. 2014;61:426-429.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 10]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
55.  Alkhoury F, Diaz D, Hidalgo J. Acute acalculous cholecystitis (AAC) in the pediatric population associated with Epstein-Barr Virus (EBV) infection. Case report and review of the literature. Int J Surg Case Rep. 2015;11:50-52.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 19]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
56.  Pawłowska-Kamieniak A, Mroczkowska-Juchkiewicz A, Gołyska D, Kominek K, Pac-Kozuchowska E. Acute acalculous cholecystitis in a 17-year-old girl with Epstein-Barr virus infection. Prz Gastroenterol. 2015;10:54-56.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 7]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
57.  Majdalani M, Milad N, Sahli Z, Rizk S. Acute acalculous cholecystitis in a Lebanese girl with primary Epstein-Barr viral infection. BMJ Case Rep. 2016;2016.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 6]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
58.  Gomes MM, Antunes H, Lobo AL, Branca F, Correia-Pinto J, Moreira-Pinto J. Acute Alithiasic Cholecystitis and Human Herpes Virus Type-6 Infection: First Case. Case Rep Pediatr. 2016;2016:9130673.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 2]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
59.  Ismaili-Jaha V, Toro H, Spahiu L, Azemi M, Hoxha-Kamberi T, Avdiu M, Spahiu-Konjusha S, Jaha L. Gallbladder ascariasis in Kosovo - focus on ultrasound and conservative therapy: a case series. J Med Case Rep. 2018;12:8.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 4]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
60.  Aguilera-Alonso D, López Medina EM, Del Rosal T, Villota Arrieta J, Escosa-García L, García-Hortelano M. Acalculous Cholecystitis in a Pediatric Patient With Plasmodium Falciparum Infection: A Case Report and Literature Review. Pediatr Infect Dis J. 2018;37:e43-e45.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 5]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
61.  Yi DY, Kim JY, Yang HR. Ultrasonographic Gallbladder Abnormality of Primary Epstein-Barr Virus Infection in Children and Its Influence on Clinical Outcome. Medicine (Baltimore). 2015;94:e1120.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 10]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
62.  Tsunoda T, Inui A, Iwasawa K, Oikawa M, Sogo T, Komatsu H, Ito Y, Fujisawa T. Acute liver dysfunction not resulting from hepatitis virus in immunocompetent children. Pediatr Int. 2017;59:551-556.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 8]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
63.  Poddighe D. Epstein-Barr virus hepatitis: Importance of PCR assay/serology and significance of γ-GTP. Pediatr Int. 2017;59:947.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 3]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
64.  Mourani S, Dobbs SM, Genta RM, Tandon AK, Yoffe B. Hepatitis A virus-associated cholecystitis. Ann Intern Med. 1994;120:398-400.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 48]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
65.  Klar A, Branski D, Nadjari M, Akerman MY, Shoseyov D, Hurvitz H. Gallbladder and pancreatic involvement in hepatitis A. J Clin Gastroenterol. 1998;27:143-145.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 9]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
66.  Huffman JL, Schenker S. Acute acalculous cholecystitis: a review. Clin Gastroenterol Hepatol. 2010;8:15-22.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 196]  [Cited by in F6Publishing: 212]  [Article Influence: 15.1]  [Reference Citation Analysis (0)]
67.  Yasuda H, Takada T, Kawarada Y, Nimura Y, Hirata K, Kimura Y, Wada K, Miura F, Hirota M, Mayumi T. Unusual cases of acute cholecystitis and cholangitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14:98-113.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 39]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
68.  Deitch EA, Engel JM. Acute acalculous cholecystitis. Ultrasonic diagnosis. Am J Surg. 1981;142:290-292.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 49]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
69.  Mirvis SE, Whitley NO, Miller JW. CT diagnosis of acalculous cholecystitis. J Comput Assist Tomogr. 1987;11:83-87.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 42]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
70.  Cornwell EE 3rd, Rodriguez A, Mirvis SE, Shorr RM. Acute acalculous cholecystitis in critically injured patients. Preoperative diagnostic imaging. Ann Surg. 1989;210:52-55.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 61]  [Cited by in F6Publishing: 65]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
71.  Ziessman HA. Functional hepatobiliary disease: chronic acalculous gallbladder and chronic acalculous biliary disease. Semin Nucl Med. 2006;36:119-132.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 30]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
72.  Gu MG, Kim TN, Song J, Nam YJ, Lee JY, Park JS. Risk factors and therapeutic outcomes of acute acalculous cholecystitis. Digestion. 2014;90:75-80.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 24]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
73.  Soria Aledo V, Galindo Iñíguez L, Flores Funes D, Carrasco Prats M, Aguayo Albasini JL. Is cholecystectomy the treatment of choice for acute acalculous cholecystitis? A systematic review of the literature. Rev Esp Enferm Dig. 2017;109:708-718.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 13]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
74.  Punia RP, Garg S, Bisht B, Dalal U, Mohan H. Clinico-pathological spectrum of gallbladder disease in children. Acta Paediatr. 2010;99:1561-1564.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 15]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
75.  Croteau D, Signer RD, Chaet MS. Acalculous cholecystitis in a two year old. JSLS. 2001;5:183-185.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  McNaughton C, Morrow S, Cico SJ. Acalculous cholecystitis in a healthy 4-year-old boy. Am J Emerg Med. 2011;29:962.e1-962.e2.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
77.  Karkera PJ, Sandlas G, Ranjan R, Gupta A, Kothari P. Acute acalculous cholecystitis causing gall bladder perforation in children. J Indian Assoc Pediatr Surg. 2010;15:139-141.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 13]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
78.  Muta Y, Odaka A, Inoue S, Komagome M, Beck Y, Tamura M, Arai E. Acute acalculous cholecystitis with eosinophilic infiltration. Pediatr Int. 2015;57:788-791.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 3]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
79.  Rodà D, Huici M, Ricart S, Vila J, Fortuny C, Alsina L. Cholecystitis and nephrotic syndrome complicating Epstein-Barr virus primary infection. Paediatr Int Child Health. 2017;37:74-77.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 5]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
80.  Ng JY, Gu J. Conservative Management of Acalculous Cholecystitis in a Seven-year-old Child. Cureus. 2018;10:e2092.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 3]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
81.  Chirdan LB, Iya D, Ramyil VM, Sule AZ, Uba AF, Ugwu BT. Acalculous cholecystitis in Nigerian children. Pediatr Surg Int. 2003;19:65-67.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 8]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
82.  Huang SC, Yang YJ. Septic shock and hypofibrinogenemia predict a fatal outcome in childhood acute acalculous cholecystitis. J Pediatr Gastroenterol Nutr. 2011;53:548-552.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 8]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
83.  Rijcken JM. Acute acalculous cholecystitis in children. East Cent Afr J Surg. 2000;5:31-34.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Schaefer CM, Towbin RB, Aria DJ, Kaye RD. Safety and effectiveness of percutaneous cholecystostomy in critically ill children who are immune compromised. Pediatr Radiol. 2016;46:1040-1045.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 5]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
85.  Lu YA, Chiu CH, Kong MS, Wang HI, Chao HC, Chen CC. Risk factors for poor outcomes of children with acute acalculous cholecystitis. Pediatr Neonatol. 2017;58:497-503.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 9]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
86.  Gomi H, Solomkin JS, Schlossberg D, Okamoto K, Takada T, Strasberg SM, Ukai T, Endo I, Iwashita Y, Hibi T. Tokyo Guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2018;25:3-16.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 160]  [Cited by in F6Publishing: 199]  [Article Influence: 33.2]  [Reference Citation Analysis (0)]
87.  van Dijk AH, de Reuver PR, Tasma TN, van Dieren S, Hugh TJ, Boermeester MA. Systematic review of antibiotic treatment for acute calculous cholecystitis. Br J Surg. 2016;103:797-811.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 27]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]