Acalculous acute cholecystitis during the course of an enteroviral infection

Abstract

Gallbladder diseases are uncommon in children. Acalculous acute cholecystitis, although rare, is the most frequent form of acute cholecystitis in childhood. In acalculous acute cholecystitis, clinical presentation and laboratory findings are unspecific, making the diagnosis challenging. Abdominal ultrasonography is the first-line exam. Most cases of paediatric acalculous acute cholecystitis have been described in critically ill patients, but can occur in previously healthy children, without underlying diseases or severe conditions. The authors present a clinical report of a child with acalculous acute cholecystitis and enteroviral infection. Diagnosis, treatment, clinical course and prognosis are described. Pathophysiology, aetiology, diagnosis and treatment of acalculous acute cholecystitis are also discussed.

Background

Acalculous acute cholecystitis (AAC) is an inflammation of the gallbladder that occurs in the absence of gallstones.^1–3 AAC is rarely seen in the paediatric population.¹ However, it is the most frequent form of acute cholecystitis in this age group, representing 30% to 70% cases.^1–3 In adults, AAC causes only 2% to 15% of acute cholecystitis cases.⁴

Although most cases of paediatric AAC have been associated with life-threatening conditions, (eg, multiple trauma, sepsis, extended burns, post major surgery, bone marrow transplantation, chemotherapy), they can occur in healthy children, without underlying and/or severe disease.^{1 3} Most of these episodes occur during systemic infectious diseases.¹ Acute cholecystitis due to viral infectious factors is reported to be extremely rare among the medical literature.⁵

Since the clinical picture and laboratory findings are nonspecific, the index of suspicion is often very low. Abdominal ultrasound is the most useful exam.¹ Diagnostic difficulties may result in either unnecessary surgical procedures or delayed diagnosis, leading to complications such as empyema, gangrene or perforation of the gallbladder.^{5 6}

The authors present a clinical report of a child with AAC during the course of an enteroviral infection.

Case presentation

A 20-month-old boy was admitted to hospital with a 24 hours history of anorexia, irritability, vomiting and abdominal pain. Emesis was not associated with diarrhoea. He had been observed in the emergency department (ED) 5 days earlier, due to fever (a single episode) and a generalised micropapular and vesicular rash with palmoplantar and mucosal involvement (petechial rash on the forearms and abdomen, oropharynx with vesicles on the anterior pillars and palatal petechiae). He was diagnosed with hand-foot-and-mouth disease. On admission, he presented with irritability, but was clinically stable (axillary temperature 35.8°C, blood pressure 120/72 mm Hg, heart rate 96 beats per minute and breathing rate 26 breaths per minute). On physical examination he still presented with the previously described generalised rash. He was anicteric and appeared well-hydrated. Cardiovascular and respiratory examination was unremarkable. Abdominal examination revealed hepatomegaly (palpable liver 5 cm below the costal margin) associated with moderate abdominal tenderness on the right quadrants and a positive Murphy’s sign. The spleen was not palpable. Family history and epidemiological data were unremarkable.

Investigations

Laboratory tests were normal, all within reference limits, and included: complete blood count (white cell count 10000/mm³, platelets 192000/mm³, haemoglobin 12.1 mg/dL), liver enzymes alanine aminotransferase 36 mU/L (normal values [n.v.] 5 to 45 mU/L) and aspartate aminotransferase 38 mU/L (n.v. 5 to 60 mU/L), lactate dehydrogenase 722 UI/L (n.v. 500 to 920 UI/L), alkaline phosphatase 180 UI/L (n.v. 145 to 320 UI/L), total bilirubin 3.1 μmol/L (n.v. <22 μmol/L), direct bilirubin 3.1 μmol/L (n.v. 0 to 7 μmol/L), gamma GT 15 UI/L (n.v. 12 to 58 UI/L), C-reactive protein 1.52 mg/dL (n.v. <0.05 mg/dL), procalcitonin 0.06 ng/mL (n.v. <0.5 ng/mL), lipase 27 UI/L (n.v. 23 to 300 UI/L), amylase 47 UI/L (n.v. 30 to 110 UI/L) and urine dipstick test with ketonuria.

Abdominal ultrasound showed a slightly enlarged liver with a very distended gallbladder, measuring approximately 7.3 cm in diameter (n.v. 4.2±0.6 cm), with slight parietal thickening and a thin layer of pericholecystic fluid, with no changes in content (figure 1). There was no evidence of gallstones or biliary tract enlargement. Serological tests for enterovirus and coxsackievirus showed a positive IgM and negative IgG. Serological testing for antibodies to the enterovirus virus was performed by using ELISA test. Serologies for cytomegalovirus, Epstein-Barr virus (EBV), parvovirus B19 and adenovirus were negative for recent or previous infection. Blood culture and stool cultures were negative. Serum immunoglobulin levels (G, A, M and E) were normal.

Figure 1.

Abdominal ultrasound showed a very distended gallbladder, measuring approximately 7.3 cm in diameter, with slight parietal thickening and a thin layer of pericholecystic fluid, with no changes in content.

Differential diagnosis

AAC has been associated with a large variety of infectious agents including viruses, bacteria, yeasts and parasites.⁷ In previously healthy children, hepatitis A virus and EBV infections are the most frequently found in this age group.^{1 7}

In this case, the diagnosis of AAC was assumed in association with coxsackievirus infection.

Treatment

Medical management was started, with intravenous fluid therapy and adequate analgesia. Antibiotic therapy (cefoxitin 160 mg/kg/day) was discontinued after 3 days’ time when the viral aetiology was confirmed by serology.

Outcome and follow-up

The patient’s symptoms improved within 3 days, and he recovered without complications. He was discharged 5 days after admission. Seven weeks later, abdominal ultrasound was almost normal, with slight hepatosplenomegaly. During a 9 month follow-up, the patient remained asymptomatic, with no evidence of AAC recurrence.

Discussion

We describe a case of AAC associated with coxsackievirus hand-foot-and-mouth disease. Enteroviruses are among the most common and significant causes of infectious illness in infants and children. Coxsackievirus A16 is the primary aetiologic agent of hand-foot-and-mouth disease, but other enteroviruses have been implicated.⁸

AAC is an inflammatory process of the gallbladder in the absence of demonstrated gallstones.^{1 9}

Although uncommon in infants and children, AAC has long been recognised among the paediatric population, from neonates to adolescents.^{1 9 10}

AAC is usually observed in the setting of critically ill patients but, in most recent years, it has been reported in previously healthy children. Yi et al,¹ analysed retrospectively a total of 131 children diagnosed with AAC. Systemic infectious diseases such as Epstein-Barr virus infection were the most common aetiology for AAC and were identified in 38% of all children. Only one case was observed during an enteroviral infection. Recently, Lu et al ⁴ presented similar results in a review of 147 paediatric patients. AAC was associated with various illnesses, including infectious diseases (70%), systemic diseases (13%) and malignancy (11%). Viral pathogens were found in 54 patients, mostly Epstein-Barr virus (32, 22%) and cytomegalovirus (10, 7%). No case of AAC associated with enterovirus was reported.⁴

The pathophysiology of AAC remains poorly understood. Gallbladder ischaemia seems to be a main event, especially in sepsis, trauma and burns.^{1 2} Regarding the pathogenesis of infectious AAC in healthy children, as opposed to ill patients, only a few or no predisposing factors are usually present. In sick children, dehydration due to vomiting, diarrhoea and/or decreased appetite/prolonged fasting are often observed and can affect gallbladder depletion and lead to bile stasis, and thus, the possible occurrence of cholestasis.^{2 11} Furthermore, bile stasis may alter chemical bile composition and promote gallbladder mucosal injury.³ The pathogenesis of AAC in the course of viral infection is unclear and could result from this complexity of factors (effect of proinflammatory mediators, reperfusion injury, cholestasis, etc).⁴

AAC diagnosis is often challenging because of the lack of specific clinical features.¹ Ultrasound is the most reliable and accurate method for the early diagnosis of AAC, even in critically ill patients.¹ In recent years, various ultrasonography criteria for the diagnosis of AAC have been established. Imaging criteria such as gallbladder wall thickening over 3 mm, distention of the gallbladder more than 5 cm in transverse diameter, localised tenderness, pericholecystic fluid and sludge have been used for the diagnosis of AAC. The combination of two major criteria, or one major criteria and two minor criteria satisfy the ultrasound diagnosis of AAC.^{1 3 11} In our patient, distension of the gallbladder, wall thickening and pericholecystic fluid were the criteria for diagnosis.

Although in adults AAC is treated with surgery, such as cholecystectomy or percutaneous cholecystectomy, in paediatric patients conservative management is the first choice.³

Following recommendations, antibiotic treatment with cefoxitin was started for 3 days, but this was interrupted as soon as coxsackievirus aetiology was ascertained and sepsis was excluded.

In conclusion, AAC may occur during the course of coxsackievirus infection in hand-foot-and-mouth disease and it should be considered in the differential diagnosis of abdominal pain in children. The benign clinical course, with medical management, reinforces the importance of a prompt and certain diagnosis of AAC owing to a viral condition, in order to avoid unnecessary surgical procedures. Close follow-up should be performed to assure complete recovery.

Learning points.

• Acalculous acute cholecystitis (AAC) may present in previously healthy children.

• AAC may be associated with common infections, including enteroviral illnesses.

• AAC may be associated with viral infections and the clinical presentation may be not specific.

• The absence of increased markers of cholestasis does not exclude the diagnosis of AAC.

• Ultrasound is the most sensitive and practical diagnostic tool for ACC in children.