Acute acalculous cholecystitis in dengue fever: a case series.

Dengue has rapidly emerged as a significant threat to public health since the 1950s, and is currently the fastest spreading mosquito-borne disease globally. The World Health Organization (WHO)[ 1 ] estimates that up to 50–100 million dengue infections occur annually, with over one-third of the world’s population being at risk. Despite an aggressive vector-control programme, dengue remains hyperendemic in Singapore, largely owing to the tropical climate and high population density. Major dengue epidemics have plagued Singapore over the years, with public health costs of each outbreak estimated to be over USD 40 million. In 2019, close to 16,000 cases[ 2 ] of dengue were reported in Singapore — the highest number of annual cases in over 5 years. The clinical spectrum of dengue ranges from a mild, self-resolving illness with fever, rash and thrombocytopenia to severe life-threatening disease characterised by vascular leakage, shock and haemorrhage. Treatment of dengue is primarily supportive, as no effective therapeutic currently exists. However, with rising disease burden, the incidence of atypical manifestations of dengue fever, such as acute acalculous cholecystitis (AAC), has increased. Despite this, dengue-associated AAC has rarely been reported in the literature — only a few descriptive studies[ 3 4 5 ] and case reports were found in major literature over the past 15 years. Besides two individual case reports from 2005[ 6 ] and 2006,[ 7 ] data on the distribution, progression and outcomes of patients presenting with dengue-associated AAC in Singapore are lacking. This article aimed to consolidate and review the clinical course and management of 12 cases identified in our institution from 2006 to 2015.

Medical and imaging records of patients presenting to Singapore General Hospital between 2006 and 2015 with dengue fever and clinical suspicion of cholecystitis were reviewed retrospectively. Dengue was confirmed in patients with a positive serum dengue IgM (Focus Diagnostics IgM Capture DxSelect, Focus Diagnostics, Herndon, VA, USA), dengue polymerase chain reaction (PCR; an inhouse assay based on pan-dengue primer sequences) or NS1 antigen (Bio-Rad Platelia Dengue NS1, Bio-Rad, Singapore). Twelve cases of dengue-associated AAC were identified by positive dengue laboratory testing, presence of clinical signs consistent with acute cholecystitis according to the Tokyo Guidelines for Acute Cholecystitis and radiological findings matching ultrasonography or computed tomography (CT) imaging criteria, in addition to the absence of cholelithiasis on imaging. Statistical analysis was performed using IBM SPSS Statistics version 25 (IBM Corp, Armonk, NY, USA). The study was approved by the Singhealth Centralised Institutional Review Board (Ref. No.: 2018/3204).

In our institution, there were 6931 admissions for dengue fever during the study period (2006–2015), of which 12 (0.17%) were diagnosed with dengue-associated AAC. Seven (58.3%) patients were male. The mean ± standard deviation (SD) age was 49 ± 10.2 years. The mean ± SD length of stay (LOS) was 5 ± 1.9 days in patients who developed dengue-associated AAC, while patients without AAC had a mean ± SD LOS of 3.9 ± 2.3 days. A Mann–Whitney U test showed significant increase (u = 26,703, P = 0.03) in LOS in patients who developed AAC (median 4.5 days) as compared to those who did not (median 4.0 days). All 12 patients presented with right hypochondrial pain and fever on admission. Murphy’s sign was positive in five (41.7%) patients. Two (16.7%) patients presented with bleeding manifestations (epistaxis, gum bleeding and petechiae). Pleural effusion was noted on the chest radiographs of eight (66.7%) patients, and ascites was noted in five (41.7%) patients, suggesting presence of significant plasma leakage. Other presenting signs and symptoms are shown in Table 1 . None of the patients had diabetes mellitus, ischaemic heart disease, chronic kidney disease or underlying malignancy. Only one patient had hypertension. Presenting signs/symptoms of patients ( N =12). Seven (56.3%) patients underwent ultrasonography, while five (41.6%) underwent CT imaging. Radiological findings are shown in Table 2 . Gallbladder wall thickening was noted in all 12 patients. The mean ± SD gallbladder wall thickness was 5.82 ± 0.31 mm. Imaging findings. CT: computed tomography, US: ultrasonography The results of liver function tests and blood tests performed during hospital stay are detailed in Table 3 . In particular, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels increased, while the albumin levels fell. Other abnormalities included thrombocytopenia, prolonged activated partial thromboplastin time (APTT) duration as well as increased C-reactive protein (CRP) levels. Blood cultures were performed in ten patients and none were found to be bacteraemic. Results of blood and liver function tests. a Data presented as mean±standard deviation. *Values that are above or below normal ranges. DHF: dengue haemorrhagic fever, DSS: dengue shock syndrome, NA: not applicable, SD: standard deviation One (8.3%) patient met the criteria for dengue haemorrhagic fever (DHF) and one (8.3%) patient progressed to dengue shock syndrome (DSS) based on WHO 1997 dengue classification. The patient with DHF also had hypertension and received intravenous (IV) hydration, while the patient with DSS received IV antibiotics and platelet transfusion. Four (33.3%) patients were treated conservatively with IV hydration, while eight (66.7%) received empirical IV antibiotics. Out of three patients with severe thrombocytopenia, two received platelets transfusion and one received cryosupernatant plasma transfusion. None required surgery or invasive interventional procedures, and all 12 patients were discharged uneventfully.

Acute acalculous cholecystitis is defined as “an acute necroinflammatory disease of the gallbladder in the absence of cholelithiasis”. Owen and Jain[ 8 ] summarised the various conditions that predispose to it, from systemic sepsis to acute viral infection, as commonly associated risk factors. Common but nonspecific clinical findings include right hypochondrial pain, fever and abnormal liver tests.[ 9 ] This is consistent with the clinical presentation of our 12 patients. Severe complications including gangrene, perforation and empyema occur in 6%–82% of people with AAC,[ 10 ] and early interventions, such as cholecystectomy and cystostomy, are often proposed.[ 11 ] While AAC is associated with high mortality rates of up to 30%, this may be an epiphenomenon of the underlying severity of illness and is rarely the primary cause of death.[ 12 ] Diagnostic ultrasonography remains the imaging modality of choice with up to 100% specificity.[ 13 ] However, CT may aid in the diagnosis of AAC due to its high sensitivity, and it may be considered when other abdominal diseases are suspected.[ 14 15 ] A few mechanisms have been hypothesised in the pathogenesis of AAC. Firstly, biliary stasis may result in altered bile composition, promoting gallbladder mucosal injury. Secondly, multiple arterial occlusions and microcirculatory disruption lead to gallbladder ischaemia, which is central in the development of AAC. Lastly, release of vasoactive mediators, such as proinflammatory eicosanoids, stimulates inflammation and coagulation.[ 14 ] While the cause for development of AAC from dengue virus remains uncertain, it has been postulated that direct viral invasion of the gallbladder may be responsible for oedema and exudation.[ 4 ] The first documentation of AAC as an atypical manifestation of dengue fever was in 2000.[ 16 ] Since then, there have been a few case reports and studies detailing the occurrence, with incidence rates varying from 6%[ 17 ] to 52%.[ 5 ] The stark difference in incidence rates may be due to different diagnostic criteria, especially since the clinical findings of AAC are often nonspecific. The mean LOS of our patients was 5 ± 1.9 days, which is comparable to that of 5.1 ± 1.8 days reported previously by Sharma et al .[ 5 ] also reported a significant increase in LOS for patients with dengue fever and AAC. In our institution, a significantly longer LOS (u = 26,703, P = 0.03) was likewise observed in patients admitted with dengue-associated AAC. Laboratory findings commonly associated with dengue include neutropenia, lymphocytosis, increased concentrations of liver enzymes and thrombocytopenia.[ 4 ] Mean AST (315.3 ± 208.9; normal range: 12–42 U/L), ALT (178.8 ± 113.6; normal range: 6–66 U/L) and ALP (119.2 ± 53.8; normal range: 39–99 U/L) levels were raised and thrombocytopenia (60.8 ± 35.1; normal range: 140–440 × 10 9 /L) was noted in our patients. In addition, low mean albumin levels (32.25 ± 2.6; normal range: 40–51 g/L) and high CRP levels (24.0 ± 17.3; normal range: 0–3 mg/dL) were also noted. Sonographic findings, such as thickened gallbladder wall, pleural effusion and ascites, were also commonly cited.[ 3 4 ] In our patients, gallbladder wall thickening was the most common feature (100%), followed by positive sonographic Murphy’s sign (42.9%) and pericholecystic fluid collection (41.2%). Ascites and pleural effusion occurred in 41.7% and 66.7% of our patients, respectively. Previous studies suggested that gallbladder wall thickening could be an indicator of ongoing plasma leakage,[ 18 ] and that a positive correlation exits between wall thickness and the development of DSS.[ 19 ] However, this was not observed in our study. Only one patient developed DSS and the gallbladder wall thickness was 4.61 mm (normal range <3 mm), which was below the mean ± SD gallbladder wall thickness (5.82 ± 0.31 mm) in our study. The usual treatment for AAC includes immediate cholecystostomy and/or cholecystectomy to prevent the feared complications of gangrene, empyema and perforation.[ 12 ] However, this does not appear to hold true for dengue-associated AAC. All of our 12 cases recovered without surgical intervention. Treatment was conservative and involved IV hydration, antibiotics and transfusion of blood products. However, a recently published randomised controlled trial of dengue patients has shown no benefit in the use prophylactic platelet transfusions as compared to supportive care alone in the absence of bleeding manifestations, and it may instead be associated with increased adverse events.[ 20 ] In dengue fever, AST and ALT levels typically rise in the first 8 days of illness, but gradually decline and normalise by the third week.[ 21 ] Gallbladder wall thickening and ascites also resolve completely with recovery of acute dengue. It appears that surgical treatment is generally not indicated in dengue-associated AAC in the absence of complications such as gallbladder perforation. This is supported by the experience of others.[ 3 5 16 17 18 19 ] Surgical intervention in dengue-associated AAC may instead lead to unnecessary complications, such as those from otherwise avoidable substantial blood transfusions, and significantly prolonged hospitalisation.[ 22 ] This study was not without limitations. Our study was done retrospectively and information was dependent on the accuracy of the medical records. While the imaging criteria have been well established, clinical signs of dengue-associated AAC are nonspecific and diagnostic criteria vary among studies.[ 8 14 ] This may have led to the large differences in incidence rate among published studies. For our study, we referred to Tokyo Guidelines for Acute Cholecystitis[ 23 ] and specific imaging criteria adapted from Huffman et al .[ 12 ] for the definite diagnosis of dengue-associated AAC [Supplemental Digital Appendix ]. As the duration between the onset of disease and admission to the hospital was variable and the exact duration of individual symptoms was not always specified in the patients notes, the true values of various clinical parameters may not have been determined precisely. For example, gallbladder wall thickness on imaging may be underestimated if sonography was done before or after the plasma leakage phase, around the time of defervescence.[ 24 ] In 2009, revised WHO guidelines for dengue severity classification[ 1 ] were published. Under the new classification guidelines, dengue fever is no longer classified as DHF and DSS. The new classification describes the severity of dengue fever based on presence of warning signs. However, the presence of such warning signs was not documented uniformly in the cases analysed and we were unable to classify our patients based on the new guidelines. Nevertheless, classifying our patients based on the 1997 dengue fever guidelines[ 25 ] allowed meaningful comparisons with other studies that adopted the same dengue classification guidelines. In conclusion, we found that dengue-associated AAC appears to be a distinct entity from other forms of AAC, and if uncomplicated, should be treated conservatively without the need for urgent surgical intervention. Nil. Kalimuddin S is a member of the SMJ Editorial Board and was thus not involved in the peer review and publication decisions of this article. Appendix at http://links.lww.com/SGMJ/A116