Surgical treatment of acute cholecystitis in patients with confirmed COVID-19:Ten case reports and review of literature

INTRODUCTION

A novel coronavirus,severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China,in December 2019,causing a new disease named coronavirus disease 2019 (COVID-19)[1].

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Research concerning postoperative outcomes of confirmed COVID-19 patients revealed unfavorable postoperative results with increased morbidity,pulmonary complications and mortality[2-5].

Several studies have described gastrointestinal symptoms in patients with COVID-19,with nearly 25% of patients referring abdominal pain[6].Association with other gastrointestinal complications for example,liver injury and late cholestasis,have been reported[7].Concerning the gallbladder,some studies have described the presence of acute ischemic gangrenous cholecystitis,with or without perforation,and with or without associated cholelithiasis[8-30].Studies have suggested that COVID-19 is associated with more aggressive presentation of acute cholecystitis[15,19,24,27,28].

The guidelines for the treatment of acute cholecystitis before the pandemic recommended early laparoscopic cholecystectomy (Lap-C) for patients with mild acute cholecystitis as the treatment of choice[31-33].For patients with moderate acute cholecystitis the treatment of choice is urgent/early Lap-C when advanced laparoscopic techniques are available.The indications for urgent Lap-C in confirmed COVID-19 patients should not differ from those without COVID-19[19].

Since the beginning of the pandemic in 2020,several surgical societies have published their recommendations to treat acute cholecystitis[2,34].The firsts recommendations were to avoid surgeries and to adopt a non-operative management when possible[28,35].The finding of virus particles in the peritoneal fluid and the idea that pneumoperitoneum could allow the transmission of virus led many surgical societies to publish recommendations for gastrointestinal laparoscopic surgery[34,36-38].More recent recommendations sustain that laparoscopy is not more likely to spread the COVID-19 infection than open surgery,and minimally invasive surgery provides better outcomes that laparotomy[2].

Since acute cholecystitis represents a very frequent cause of hospital admission worldwide[39],it is important to know the perioperative outcomes of patients with confirmed COVID-19 and cholecystitis,also it is important to know what to expect during surgeries.

Several studies have described the presentation of acute cholecystitis concomitant with a SARS-CoV-2 infection.A literature review of the research concerning COVID-19 and acute cholecystitis is summarized in Table 4.We have noticed that the majority of studies that have been published during the pandemic are case reports and letters to the editor (see Table 4).The first case report of histopathological findings of an acute ischemic gangrenous cholecystitis as a late complication in a COVID-19 patient was published by Bruni[21].Since then,the description of gangrenous cholecystitis in patients with COVID-19 has been found in at least six other studies[15,18,19,24,27,28].In our series,3 patients had wall ischemia and segmental necrosis,and 5 patients had complete transmural necrosis.Of note,some of these case reports outlined the presence of gangrenous cholecystitis but without cholelithiasis (acalculous)[18,19,27].In our series,only one patient presented with acalculous cholecystitis,and the rest of the patients had cholelithiasis.This could represent a different physiopathological pathway that should be further investigated.Nevertheless,patients with both etiologies required cholecystectomy.

CASE PRESENTATION

Chief complaints

We included symptomatic and asymptomatic SARS-CoV-2 positive patients (asymptomatic carriers) who required urgent/early cholecystectomy.During the pandemic all the patients that were admitted to our hospital were screened for SARSCoV-2 infection.

Regarding the chief complaints,patients presented with the characteristic right upper quadrant pain related to acute cholecystitis.

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History of present illness

All patients had concomitant acute cholecystitis with SARS-CoV-2 infection.We included patients with the SARS-CoV-2 infection confirmed either by reversetranscriptase polymerase chain reaction (RT-PCR) assay of a nasopharyngeal swab or a rapid antigenic test.Several variables were recorded including demographic parameters and preoperative quick Sequential Organ Failure Assessment (qSOFA) score[40].Data is shown in Table 1.

History of past illness

Of the ten patients,four had history of past illness.The most frequent comorbidity was hypertension (=4).The complete list of comorbidities is presented in Table 1.

Personal and family history

Regarding the timing of COVID-19 diagnosis,nine patients were diagnosed preoperatively and one was diagnosed postoperatively.Of the 10 patients,four were asymptomatic SARS-CoV-2 carriers.The rest of patients (=6) presented with symptomatic disease and preoperative CT scans with COVID-19 pneumonia (bilateral ground-glass opacities with consolidation).

Physical examination

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On physical examinations patients had right upper quadrant pain (=10),right upper quadrant mass (=6),and positive Murphy′s sign (=10).

Demographic data included age (years),gender,body mass index in kg/m,comorbidities,smoking status,American Society of Anesthesiology classification.The preoperative qSOFA score was calculated and we divided the patients in high risk (＞2 point) or not high risk patients (0-1 points).

Laboratory examinations

During laparoscopy we filtered the pneumoperitoneum through filters able to remove most viral particles as suggested by several authors[2,42,43].

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Imaging examinations

All patients underwent chest computed tomography (CT) scans prior to surgery.Also,all patients underwent gallbladder ultrasound.We diagnosed acute cholecystitis according to Tokyo Guidelines (TG18) ultrasound criteria (thickened gallbladder wall,enlarged gallbladder,pericholecystic fluid collection)[32,41].

FINAL DIAGNOSIS

The personal and family history was noncontributory.

We found in the present study that patients with confirmed SARS-CoV-2 infections with concomitant acute cholecystitis tended to have high grades on the Parkland grading scale (including gallbladder perforation,empyema and total wall necrosis),difficult Lap-C with an increased need for a bail-out procedure (open conversion or subtotal cholecystectomy),high ICU admission rates,high rates of postoperative biliary leaks that required ERCP (with biliary stent placement),and prolonged length of hospital stay.

resolution of cholangitis and pancreatitis,respectively.

TREATMENT

All surgeries were performed at a COVID-19 dedicated operating theater and all the medical staff were equipped with personal protective equipment.Laparoscopic cholecystectomies were performed with a 3 or 4 trocar technique depending the case,using a 12-mm umbilical trocar (optical),a 12-mm trocar in the sub-xiphoid area,and a 5-mm in the right flank.We performed diagnostic laparoscopy and we graded the intraoperative findings according with the Parkland scale.After that,bile and purulent collections were drained and intraabdominal adhesions were taken down.The decision to perform a bail-out procedure was done when the critical view of safety was difficult to achieve.In our hospital,we employ the reconstituting subtotal cholecystectomy or the open conversion as bailout procedures.The reconstituting subtotal cholecystectomy consisted in making an incision in the gallbladder,aspirating the contents including the stones,removing the peritonealized portion of the gallbladder,except the lowest portion (infundibulum and Hartmann′s pouch),and partially excising the posterior wall adherent to the liver.After that,the lowest part of the gallbladder is closed with sutures obliterating the cystic duct,leaving a closed gallbladder remnant[15,41].

Preoperative laboratory examinations are shown in Table 1.Of relevance,the mean preoperative C-reactive protein level was 20.1 mg/dL,the mean total bilirubin was 1.29 mg/dL,and the mean ferritin level was 565 ng/mL.

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Two patients required preoperative endoscopic retrograde cholangiopancreatography (ERCP).One patient had cholestasis and a type I Mirizzi syndrome was found at ERCP.The other patient had grade II acute cholangitis and required early endoscopic treatment (ERCP biliary drainage).

All patients were treated with urgent/early Lap-C.Eight surgeries were completedlaparoscopy and two patients required conversion to open cholecystectomy due to operative difficulty.

Regarding the Parkland grading scale,all patients were found to have severe inflammation (grades 3-5):Two patients had pericholecystic fluid,adhesions to the gallbladder body,hyperemia and distended gallbladder (Parkland 3);One patient had adhesions obscuring the majority of the gallbladder and one patient had Mirizzi syndrome (Parkland 4);And six patients had Parkland 5 (six patients with complete necrosis of the gallbladder body infundibulum and cystic duct,three of them with gallbladder perforation) see Figure 1.Six cases were treated with subtotal reconstituting cholecystectomy,because a critical view of safety could not be achieved.

The mean estimated blood loss (EBL) was 258 mL,the mean operative time was 133.5 min,and eight patients required intraabdominal closed drainage.

OUTCOME AND FOLLOW-UP

Operative outcomes included modality of cholecystectomy (laparoscopic,open or converted),EBL in mL,operative time in minutes,and requirement of intraabdominal drainage.We graded the intraoperative findings according with the Parkland grading scale for cholecystitis[42].Preoperative or postoperative need for ERCP and findings were registered.

Postoperative complications were classified and presented according with the Clavien-Dindo classification.The need for intensive care unit (ICU),vasopressors and invasive mechanical ventilation were recorded.The hospital length of stay (LOS) in days was registered.

Five patients developed biliary leak after subtotal cholecystectomy.Of these patients,two had low-output leak,while three patients had high-output biliary leak.Patients with low-output leaks were treated with closed suction drainage alone,while patients with high-output leaks needed ERCP with biliary sphincterotomy and biliary stent placement.The complete list of postoperative complications classified according to Clavien-Dindo is shown in Table 2.

After surgery five patients required ICU admission,and one patient was admitted preoperatively and remained in the ICU after surgery.The five patients were on invasive mechanical ventilation and vasopressor therapy.These patients developed acute respiratory distress syndrome (ARDS) related to SARS-CoV-2.One patient died after cholecystectomy and due to ARDS complications.

Considering the complete cohort of patients,the mean total LOS was 18.2 d.

The histopathological diagnosis was performed using hematoxylin-eosin (H&E) stained slides (Table 3).As demonstrated in Figure 2,H&E slides displayed the inflammatory infiltration (=10),with transmural necrosis (=5),hemorrhagic infarction (=2),mucosal ulcerations (=1),vessel obliteration with ischemia (=3),gallbladder wall perforation (=3),and acute peritonitis (=10).

DISCUSSION

We diagnosed and graded the severity of acute cholecystitis according to the 2018 TG18[32,41].All patients were diagnosed with definite acute cholecystitis according to the TG18.Regarding the severity assessment,nine patients had grade II (moderate) acute cholecystitis and one patient had grade III (severe) acute cholecystitis.Additionally,one patient was diagnosed with grade II acute cholangitis,and the other patient had concomitant mild acute pancreatitis.Both patients were operated after

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The aim of the present study was to describe the perioperative assessment and postoperative outcomes of patients with confirmed SARS-CoV-2 infection with concomitant acute cholecystitis who underwent urgent cholecystectomy.

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An editorial by Cirillo[22],reported the finding of acalculous hemorrhagic cholecystitis in a patient with a SARS-CoV-2 infection who needed emergent cholecystectomy.In our histopathological analysis we found that 2 patients had hemorrhagic changes in the gallbladder wall after surgery.Our report differs from the report of Cirillo[22],in the fact that they preoperatively diagnosed the hemorrhage by CT scan with active contrast extravasation around and inside a perforated gallbladder.The presence of hemorrhage from an inflamed gallbladder is rare and larger studies are needed to confirm an association with SARS-CoV-2 infection.

Considering the potential association of SARS-CoV-2 with gallbladder disease,several hypothesis have been formulated.One hypothesis is that the systemic inflammation,the immune system changes induced by SARS-CoV-2,and the immunotherapy employed to treat it,may contribute to the late onset of cholecystitis by proinflammatory pathways[15].Also,the findings of small-vessel thrombosis and gallbladder wall ischemia suggested a correlation with the coagulopathy and prothrombotic state induced by this coronavirus[21,44].Furthermore,it has been suggested that due to the expression of angiotensin-converting enzyme 2 receptor in gallbladder epithelial cells,SARS-CoV-2 could target that cells[45].Taking into account these inflammatory changes,we found on the histopathological examination of our patients,acute peritonitis,acute inflammatory infiltrates,as well as ischemic and necrosis associated with small vessel thrombi,and hemorrhagic changes in the gallbladder wall of our patients.

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Regarding the treatment of acute cholecystitis,some authors reported the treatment with antibiotics[46],others reported percutaneous cholecystostomy[16,26],and others published their outcomes after laparoscopic or open cholecystectomy[46,47] (Table 4).The relevance of our study is that we described the outcomes of 10 patients with positive COVID-19 tests who required urgent cholecystectomy.Urgent/early cholecystectomies were performed due to gallbladder perforation (=3) and gangrenous cholecystitis (=8),where medical treatment with antibiotics only or cholecystostomy were considered insufficient treatments[19,32,41].

Concerning the intraoperative findings,we found that patients were operated on at a very advanced stage of acute cholecystitis with severe inflammation (a Parkland score＞3);thus,the critical view of safety was very difficult to achieve.The majority of our patients required a bail-out procedure for a safe cholecystectomy.As mentioned in the results section,2 underwent conversion to laparotomy and 6 required sub-total reconstituting cholecystectomy.Of note,3 of the 6 patients who needed sub-total cholecystectomy required ERCP due to biliary leak.Leaks developed in patients with complete gangrenous cholecystitis that extended to the infundibulum and to the cystic duct.Therefore,it is important to consider that in patients with suspected gallbladder necrosis,ischemia could extend to the cystic duct,thereby increasing the risk of postoperative biliary leakage or fistula.In our series,patients who develop postoperative bile leakage where treated with ERCP.Endoscopic management of biliary leaks (sphincterotomy with or without biliary stent) is associated with more than 90% of biliary leak healing or closure[48].ERCP is currently considered the firstline treatment option for biliary leaks,specially cystic stump leaks[48].Surgeons should be aware that when treating patients with difficult cholecystectomies,the goals are to resolve the septic process and to prevent secondary damage.As reported in previous COVID-19 cases[19,21,24],as well as in our series,operated patients during this pandemic tended to have severe inflammation of the gallbladder thus increasing the risks of postoperative complications including bile duct injury.As suggested by international guidelines[41],choosing a bail-out procedure (subtotal cholecystectomy or open conversion) based on intraoperative findings is recommended to avoid a secondary damage.Both bail-out procedures have been reported to reduce bile duct injury and overall postoperative complications,although it has been recognized that laparoscopic subtotal cholecystectomy is associated with increased rates of postoperative bile leakage in comparison with open conversion[41,49].

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There are some limitations to our study that need to be mentioned.The most important limitation is that this was a single-center study with a small sample,which predisposes the study to all the biases inherent to the design (selection,information and confusion biases).Further prospective and multi-center studies should be performed and published,in order to better understand the effects of COVID-19 on acute cholecystitis.However,despite these limitations we consider that the results of this study could help us to describe some of the implications of SARS-CoV-2 infections in patients who require urgent/early Lap-C.

CONCLUSION

In conclusion,we found in the present study that patients with confirmed SARS-CoV-2 infections who presented with acute cholecystitis,tended to have a higher grade on the Parkland grading scale (including gallbladder perforation,empyema and total wall necrosis),had difficult laparoscopic cholecystectomies with an increased need for a bail-out procedure,had high rates of ICU admission,and had a prolonged length of hospital stay.As suggested by our case series and previously published literature,we advise to surgeons performing cholecystectomy in confirmed SARS-CoV-2 patients to be prepared for a difficult surgery and to consider a bail-out procedure to prevent secondary damage.

We would like to thank all medical and nurse staff dedicated to COVID-19 surgical care at our Hospital.Special thanks to Dr.Karina Flores,for sharing her surgical images.