Furqana Akhtar  ( Department of Internal Medicine, Shaukat Khanum Memorial Cancer Hospital Research Centre Lahore, Pakistan. )
Muhammad Zeeshan Siddique  ( Department of Internal Medicine, Shaukat Khanum Memorial Cancer Hospital Research Centre Lahore, Pakistan. )
Aun Raza  ( Department of Internal Medicine, Shaukat Khanum Memorial Cancer Hospital Research Centre Lahore, Pakistan. )
Shafqat Mehmood  ( Department of Internal Medicine, Shaukat Khanum Memorial Cancer Hospital Research Centre Lahore, Pakistan. )
Muhammad Aasim Yusuf  ( Department of Internal Medicine, Shaukat Khanum Memorial Cancer Hospital Research Centre Lahore, Pakistan. )
Faisal Sultan  ( Department of Internal Medicine, Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. )

Objective: To evaluate microbiological and clinical characteristics of acute cholangitis along with their impact on mortality, and to compare the role of early versus late biliary drainage in the management of cholangitis.

Methods: The retrospective study was conducted at the Shaukat Khanum Memorial Cancer Hospital Research Centre, Lahore, Pakistan, and comprised records of all patients presenting with acute cholangitis from June, 2012, to June, 2017. The risk factors, presence of bacteremia, resistance pattern of microbial pathogens and severity were assessed according to Tokyo guidelines in addition to associated mortality and recurrence at 3 months. Data was analysed using SPSS 20.

Results: Of the 230 patients, 137(59.6%) were male. The overall mean age was 56±13 years. The most common isolated organism was Escherichia coli 54(70.1%). Clinical severity (p=0.001), late biliary drainage (p=0.001) and use of multiple stents (p=0.03) were associated with increased mortality. However, in multivariable analysis, only high body mass index (p=0.01) and Tokyo severity grades II (p=0.04) and III (p=0.001) were significant factors associated with mortality.

Conclusion: Early identification of risk factors, administration of appropriate antibiotics and establishing early biliary drainage were found to be the key management steps to reduce cholangitis-related mortality.

Keywords: Cholangitis, Tokyo classification, Bacteremia. (JPMA 70: 607; 2020)

https://doi.org/10.5455/JPMA.29747

 

Introduction

 

Cholangitis is the infectious inflammation of obstructed biliary system. Clinical manifestations of cholangitis include fever (90%), right upper quadrant (RUQ) pain (70%) and jaundice (60%); the presence of these is also known as Charcot's triad, which has a sensitivity of 70-75% in establishing the diagnosis.^1,2 In more severe cases, hypotension (30%) and altered mental status (20%) can be observed, referred to as Reynold's pentad.³ The mean age at presentation is reported to be 60-70 years without any gender predominance.^4,5 The history of biliary disease, including cholelithiasis and benign or malignant strictures, is the major risk factor. Other risk factors include a prior history of biliary stent insertion, previous episodes of cholangitis, history of cirrhosis and liver abscess. Severity of cholangitis is based on Tokyo guidelines.^6,7 According to these guidelines, mild cholangitis responds to medical treatment alone, while in moderate cholangitis, there is a lack of response to medical treatment. Severe cholangitis is defined by the lack of response and presence of organ dysfunction. The spectrum of organ dysfunction includes hypotension, requiring ionotropic support, acute kidney injury, liver failure or multi-organ failure.^7-9 The management of cholangitis depends on three parameters: resuscitation, antimicrobials and biliary drainage. Biliary drainage, which is a cornerstone in the management, has been shown to have a significant impact on mortality from 50% to less than 10%.^9,10 In addition, early biliary drainage is recommended in moderate to severe cholangitis, according to Tokyo classification,^6,7 which obviously requires increased resources and cost. Bacteremia occurs in 20-80% of the patients with cholangitis^2,4 and is associated with a mortality of 10-20%.^4,9,10 Escherichia (E.) coli is the most common organism, followed by Klebsiella(K.) spp, Enterococcus spp, Pseudomonas (P.) aeruginosa and Enterobacter spp.^3,5 Empirical antibiotics play a pivotal role and can de-escalated once sensitivity data is known. However, widespread and indiscriminate use of antibiotics has altered the sensitivity pattern of micro-organisms which necessitates a change in the choice of empiric antibiotics. Moreover, in patients with malignant obstruction, the risk of empirical antimicrobial therapy failure is high as these patients may have resistant gram-negative organisms and Candida (C.) species.² Therefore, it is essential to know the native microbiology data and resistance patterns to suggest effective empirical regimen.

The current study was planned to evaluate microbiological and clinical characteristics of acute cholangitis along with their impact on mortality, and to compare the role of early versus late biliary drainage in the management of cholangitis.

 

Patient and Methods

 

The retrospective study was conducted at the Shaukat Khanum Memorial Cancer Hospital Research Centre, Lahore, Pakistan, and comprised records of all patients presenting with acute cholangitis from June, 2012, to June, 2017. After approval from the institutional review board, data of patients was selected using the keyword 'cholangitis', and all the charts were reviewed. Only data of patients with cholangitis of either gender and regardless of age was included. Diagnosis of acute cholangitis was based on any two of the three clinical characteristics; fever, jaundice (or deranged liver function test (LFT) results, and radiological evidence of biliary obstruction (biliary dilation or loss of pneumobilia in liver). Those with documented liver metastasis or having reasons of deranged LFTs other than cholangitis were excluded.

The baseline characteristics of the patients, including age, gender, body mass index (BMI),¹¹ primary diagnoses, and associated co-morbidities were recorded. Other factors, like the type of biliary stricture, according to Bismuth classification,¹² type of biliary stents (plastic versus metallic), yield of blood cultures, resistance pattern of microbial pathogens, the risk of developing cholangitis and clinical severity, according to the Tokyo guidelines,¹³ were also recorded, and similar was the case with laboratory values of bilirubin, prothrombin time / international normalised ratio (PT/INR), white blood cell (WBC) count and creatinine levels along with blood culture results and antimicrobial susceptibility of the isolated organisms.

The effect of all these factors was analysed on recurrence of cholangitis and 3-month mortality.

Primary outcome was death in 3 months from the episode of cholangitis, and the secondary outcome was recurrence of cholangitis in 3 months.

Statistical analysis was done using SPSS 20. Continuous variables were stated as mean ± standard deviation (SD), and categorical variables were computed as frequencies and percentages. Categorical variables were compared using chi square test or fisher's exact test as deemed necessary. The continuous variables were compared using independent t-test. Statistical significance was defined as two-tailed p<0.05. Multivariable logistic regression (MLR) model was used to identify the independent risk factors associated with mortality.

 

Results

 

Out of 573 data sets reviewed, 230(40.35%) were included, and, of them, 137(59.6%) were male. The overall mean age of the sample was 56±13 years. Overall, 188(80.7%) patients had prior history of biliary instrumentation, 92(40%) had a history of prior cholangitis, and 164(71.3%) were diagnosed to have distal common bile duct (CBD) stricture. Other factors, like BMI, type of biliary stricture, type of biliary stents and risk of developing cholangitis and clinical severity were also assessed (Table-1).

Moreover, 200(86.9%) patients had underlying cancer, the most common of which was pancreatic carcinoma 66(28.7%), while 30(12.17%) were non-cancer, 101(43.9%) had no co-morbidities and 56(24.3%) had multiple underlying illnesses, including diabetes and hypertension (Table-2).

Of 230 patients with cholangitis, blood cultures had been drawn in 166(72.17%) cases, and bacteremia was reported in 77(46.38%) of them. The most common isolated organisms were gram-negative bacilli 65(84.4%), predominantly E. coli 54(70.12%) (Table-3).

Clinical severity (p=0.001), late biliary drainage (p=0.001) and use of multiple stents (p=0.03) were associated with increased mortality (Table-4).

Univariable and multivariable analysis of different clinical characteristics and their impact on mortality were separately assessed (Table-5).

 

Discussion

 

Acute cholangitis is a significant cause of morbidity and mortality, especially in the elderly, and is the second commonest cause of bacteremia.^4,5 The reported risk factors for cholangitis include history of biliary stricture / obstruction, prior biliary instrumentation (Endoscopic retrograde cholangiopancreatography [ERCP] / Percutaneous transhepatic [PTC] or surgical exploration), cholelithiasis, age >70 years, history of bacteremia in the recent past and diabetes8 also were noted in the current study. Bacteremia has been reported in 20-80% cases of acute cholangitis.³ Bae et al. reported positive blood cultures in 31.6% cases and another study from India reported this to be 26%,^2,14,15 while in our study, blood culture yield was 46.38%, which was significantly higher. The isolated organisms were predominantly gram-negative bacilli, with E. coli as the commonest one, similar to previous studies.^2,3,5 There has been an increasing trend of bacterial resistance. A study showed increasing resistance to ampicillin (44.8%), 3rd generation cephalosporin (36.5%) and ciprofloxacin (42%),^2,4 and similar results have been shown by other studies from India and Barcelona.⁵ Microbiological characteristics and resistance patterns in the current study showed increase resistance to cephalosporin and quinolones. The current practice in our institutiomnis to use quinolones as empiric antibiotics in grade-1 cholangitis, considering their excellent oral absorption and good biliary penetration, but evidence of resistance to quinolones appeared to be high. However, in moderate and severe cholangitis, empirical use of piperacillin/tazobactam is in line with the sensitivity patterns (70-80% sensitive). Bacteremia in cholangitis has mortality of 10-20%, if left untreated.^5,16 In our study, mortality was 23.37% and was highest in those with polymicrobial bacteremia 75%. However, it did not show statistical significance as a predictor of mortality.

The overall mortality in acute cholangitis is reported to be 14-40%.¹⁷ In our study, it was 25.7%. In univariate analysis of the risk factors, renal insufficiency (increase creatinine value), increasing severity, late biliary drainage and use of multiple stents were identified as significant predictors of mortality, but in multivariate analysis, only high BMI and severity of grade II and III severity were statistically significant predictors of mortality. Though late biliary drainage appeared to have increased risk, it was not statistically significant in the current study. Among patients with advanced severity, those who had multi-organ failure were more at risk of dying.¹⁸ These findings are in line with previous studies except the association of increased BMI with mortality, which was observed in our study. Biliary strictures of Bismuth class III and IV are associated with significant mortality,^11,19 but it was not observed in the current study. This observation might be due to limited number of cases with proximal stricture i.e. 41/230 (17.82%). The mortality in proximal strictures was 18/42 (42.8%) compared to distal strictures 36/160 (22.5%), with class-I having6/14 (42.85%), class II 7/12 (58.33%), class III 4/ 8 (50%) and class IV 2/8 (25%) deaths.

Clinical severity of cholangitis is based on Tokyo guidelines,¹³ which state that early biliary drainage in addition to antibiotics is needed in patient with higher grades II or III due to higher mortality in this group. However, timeframe for this early intervention was not elucidated.^20-22 Ming Tan et al. reported association between early biliary drainage (within 24-72 hours) with improved survival in moderate to severe cholangitis (30-day mortality).^23-27 Similarly, Lee F et al. reported decreased mortality with early biliary drainage (within 48 hours).¹⁴ Our study further suggests that the lack of early biliary drainage (within 24 hours) is associated with worse outcome, though results were not statistically significant in multivariable analysis. We suggest further research, preferably multicentre, to investigate this relationship because it will have important implications in terms of cost and outcome.

In terms of limitations, the current study was retrospective in nature, and mainly comprised cancer patients. It is, therefore, recommended to further investigate the matter in both cancer and non-cancer patients.

 

Conclusion

 

Increasing BMI, Tokyo grading of clinical severity and inability to establish biliary drainage were found to be important predictors of mortality, but biliary drainage within 24 hours of presentation needed to be further investigated. Due to emerging resistance to quinolones, institutional guidelines should be reviewed to suggest appropriate empirical antibiotics according to institutional and local antimicrobial sensitivity data.

 

Disclaimer: None.

Conflict of Interest: None.

Source of Funding: None.

 

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